EA014555B1 - Bcrp/abcg2 inhibitors - Google Patents

Abstract

Disclosed is a breast cancer resistant protein (BCRP/ABCG2) inhibitor. A BCRP inhibitor comprising an acrylonitrile derivative represented by the general formula (1) or a salt thereof as the active ingredient: (1) (E or Z) wherein one of R1 and R2 represents a cyano group and the other represents a hydrogen atom; Arrepresents a group selected from the groups represented by the formulae (2) to (4) below; and Arrepresents an aromatic hydrocarbon group which has a fused ring optionally substituted by a halogen atom or a group selected from the groups represented by the formulae (5) to (15) below.

Description

The invention relates to a protein inhibitor that determines resistance to breast cancer (SCCR / ABCO2).

Serious problems associated with anticancer chemotherapy include its inherent resistance to the anticancer agent, which significantly reduces the effect of the anticancer agent from the start of anticancer therapy and leads to the development of acquired resistance to the anticancer agent (i.e., to a decrease in the effect of the drug caused by it continuous continuous administration). During the study, the possibilities of overcoming such resistance to anticancer agents were studied in order to increase the effect of anticancer chemotherapy, and attempts were made to understand the various mechanisms of resistance. In particular, the expression of a drug transporter that actively transfers the anticancer agent outside the cancer cells, thus reducing the level of intracellular drug accumulation, is believed to play an important role in the development of this kind of resistance mechanism.

In particular, P-glycoprotein, which is a drug transporter discovered in the 1970s and encoded by the ΜΌΚ1 gene, is regarded as a powerful target molecule for an agent that can be used to overcome resistance to multiple drugs, since this protein causes cross-linking. resistance to many anticancer agents having various chemical structures and mechanisms of action. However, it gradually became clear that the mechanism of resistance to an anticancer agent cannot be explained on the basis of analysis of P-glycoprotein alone, thus, a need arose for the development of an agent capable of overcoming resistance, the target of which would be a different drug transporter.

With this question in 1998, a protein was discovered that determines resistance to breast cancer (SCCR, also called ABCO2, ΜΧΚ or ABCP), which is a drug transporter belonging to a group called the ATP binding cassette transporter superfamily (ABC) , to which P-glycoprotein also belongs (see non-patent document 1). SCCR has a structure that includes only one ATP binding cassette, which distinguishes it from the structure in the case of P-glycoprotein or another ABC transporter containing two ATP binding cassettes. SCCR is involved in the resistance mechanism to topoisomerase I inhibitor (e.g., irinotecan hydrochloride (CPT-11) or topotecan), topoisomerase II inhibitor (e.g. to mitoxantrone) or to a therapeutic agent acting on a specific molecule (e.g., gefitinib and imate ) At the same time, it was shown that SCCR exhibits substrate specificity different from the substrate specificity of P-glycoprotein, since SCCR does not act, for example, on paclitaxel or vincristine that are excreted by P-glycoprotein, and SCCR is involved in the excretion of the camptothecin derivative (e.g. CPT-11 or 7-ethyl-10-hydroxycamptothecin (§N-38: active metabolite of CPT-11), which is rarely excreted into the intracellular space by P-glycoprotein (see non-patent document 2) .In addition, it was suggested that VSKR in is involved in the process of limiting the bioavailability of an orally administered anticancer agent (see non-patent document 3.) In connection with the foregoing, a need arose for the development of an SCCR inhibitor capable of demonstrating an effect in overcoming resistance to an anticancer agent that cannot be overcome by traditional agents aimed at elimination of resistance, and to increase the bioavailability of the anticancer agent.

In this regard, in the present work, in order to overcome resistance to anticancer agents, many P-glycoprotein inhibitors were developed. Whereas, on the contrary, there are only a few reports on the results of a study of SCCR inhibitors, and the detected inhibitory effect was not satisfactory. In this regard, continuous attempts have been made to develop more effective inhibitors of SCCR. Examples of compounds known in the literature that show an inhibitory effect on SCCR include: a PTC derivative (fumitremorgin C) (see non-patent document 4), estrogen and antiestrogen (see non-patent document 5), and novobiocin (see non-patent document 6). The inventors of the present invention also found that a flavonoid (see Patent Document 1) and a diphenylacrylonitrile derivative (see Patent Document 2) have potent activity for inhibiting SCCR.

Moreover, with regard to derivatives of acrylonitriles containing a heterocyclic ring, there are reports of an anticancer agent activated by СУР1В1 (see patent document 3) and a 12-lipoxygenase inhibitor (patent document 4). However, no reports were found of an acrylonitrile derivative containing a heterocyclic ring that can serve as an inhibitor of SCCR, acting as an agent to overcome resistance to an anticancer agent and an agent to potentiate the effect of an anticancer agent.

Patent Document 1: XO 2004/069233.

Patent Document 2: \ XO 2004/069243.

Patent Document 3: \ XO 99/40056.

Patent Document 4: 1P-A-7-48336.

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Non Patent Document 1: Proc. Ν; ι11. Asab. 8εί. I8A, 1998, 95: 15665-15670.

Non Patent Document 2: Sapseg Kek., 1999, 59: 5938-5946.

Non Patent Document 3: 1. Syp. Opso., 2002, 20: 2943-2950.

Non Patent Document 4: Mo1. Sapseg Tieg., 2002, 1: 417-425.

Non Patent Document 5: Mo1. Sapseg Tieg., 2003, 2: 105-112.

Non Patent Document 6: Ιηΐ. 1. Sapseg, 2004, 108: 146-151.

An object of the present invention is to provide a medicament for inhibiting a protein that determines resistance to breast cancer (SCCR).

In an attempt to solve the above problems, the authors of the present invention screened compounds using cancer cells that have acquired resistance mediated by expression of SCCR and found that the acrylonitrile derivatives represented by the following formula (1) exhibit a potent SCCR inhibitory effect. It has also been found that these acrylonitrile derivatives exhibiting a SCCR inhibitory effect include novel compounds. The present invention is based on these findings.

Accordingly, the present invention relates to an SCCR inhibitor comprising, as an active ingredient, an acrylonitrile derivative represented by the formula (1):

Ai, X

P) <E or Ζ) [where one of K; and K ₂ means a cyano group, and the other means a hydrogen atom;

Ar ¹ means a group selected from the groups represented by formulas (2) to (4):

(where K7 and K8, which may be the same or different, each means a hydrogen atom, a halogen atom or a lower alkoxy group;

A means an oxygen atom, a sulfur atom, or IR ₉ ; and K ₉ represents a hydrogen atom or a lower alkyl group; Ar ² means an aromatic hydrocarbon group containing a fused ring which may be substituted by a halogen atom, or a group selected from the groups represented by formulas (5) to (15):

(I) (12) (13) (14) (15) (where K ₃ means a hydrogen atom, an oxygen atom (in the form of Ν-oxide), a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a methylsulfanyl group, a lower hydroxyalkyl a group, an aromatic hydrocarbon group which may have a substituent, or MK, (K.);

K5 and K6, which may be the same or different, each means a hydrogen atom, a lower alkyl group, which may contain a substituent, a lower hydroxyalkyl group or an aromatic hydrocarbon group, which may have a substituent, or a heterocyclic group; K ₅ and K ₆ can form, together with an adjacent nitrogen atom, a heterocyclic ring which may contain a substituent; and where the hydroxyl group in the lower hydroxyalkyl group or a heterocyclic ring substituted with a hydroxyl group or a lower hydroxyalkyl group can form an ester bond with a phosphoric acid group or its salt, or with an acyl group which may contain a substituent;

K4 means a hydrogen atom, a lower alkyl group, a phenyl group which may contain a substituent, or a benzyl group;

X is a carbon atom, CH or a nitrogen atom, provided that when A is an oxygen atom, then X cannot be a nitrogen atom); and

A, K ₇ , K ₈ and K ₉ have the meanings defined above)] or its salt.

The present invention also relates to an agent for overcoming resistance to an anticancer agent (hereinafter referred to as an agent for overcoming resistance to an anticancer agent), or to an agent for potentiating the effect of an anticancer agent (hereinafter referred to as an agent for potentiating the effect of an anticancer agent), wherein said agent includes as an active an ingredient of the above derived acrylonitrile or its salt.

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The present invention also relates to a composition of an anticancer agent containing the aforementioned acrylonitrile derivative or a salt thereof and an anticancer agent that serves as a substrate for SCCR.

The present invention also relates to the use of the aforementioned acrylonitrile derivative or a salt thereof for producing an SCCR inhibitor, as an agent for overcoming resistance to an anticancer agent or an agent for potentiating the effect of an anticancer agent.

The present invention also relates to a method of treating cancer, which is characterized by the presence of acquired resistance to a drug by a mechanism mediated by SCCR, comprising administering the aforementioned acrylonitrile derivative or a salt thereof.

Among the compounds represented by formula (1), the compounds represented by the following formula (1a) are new compounds. Thus, the present invention relates to acrylonitrile derivatives represented by the formula (1a):

(1a) (Yelig) [where one of K ₁ and K ₂ means a cyano group and the other means a hydrogen atom; Ar ¹ means a group selected from the groups represented by formulas (2) to (4):

(where K ₇ and K ₈ , which may be the same or different, each means a hydrogen atom, a halogen atom or a lower alkoxy group;

A means an oxygen atom, a sulfur atom, or IR ₉ ; and

K ₉ means a hydrogen atom or a lower alkyl group);

Ar ² means an aromatic hydrocarbon group containing a fused ring which may be substituted by a halogen atom, or a group selected from the groups represented by formulas (5) to (15)

(11) (12) (13) (14) (15) (where K _3a means a hydrogen atom (Ar ¹ means a group represented by formula (3) or (4)), a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group a methylsulfanyl group, a lower hydroxyalkyl group or an aromatic hydrocarbon group which may be substituted with a nitro group or an amino group, or LK ₅ (K ₆ );

K ₃ means a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a methylsulfanyl group, a lower hydroxyalkyl group, an aromatic hydrocarbon group which may be substituted by an amino group, or ΝΡ ₅ (Ρ ₆ ); K _3c means a hydrogen atom (Ar ¹ means a group represented by formula (3) or (4)), an oxygen atom (in the form of a Ν-oxide), a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a methylsulfanyl group, a lower hydroxyalkyl group an aromatic hydrocarbon group which may be substituted by a nitro group or an amino group, or NK ₅ (Kb);

each of K _{3 <1} , K _3e and K _{3 £} means a hydrogen atom, an oxygen atom (in the form of Ν-oxide), lower alkyl group, lower alkoxy group, halogen atom, nitro group, methylsulfanyl group, lower hydroxyalkyl group, aromatic hydrocarbon group, which may be substituted by an amino group, or NK ₅ (Kb);

K ₅ and K ₆ , which may be the same or different, each means a hydrogen atom, a lower alkyl group which may contain a substituent, a lower hydroxyalkyl group or an aromatic hydrocarbon group which may contain a substituent, or a heterocyclic group; K ₅ and K ₆ can form, together with an adjacent nitrogen atom, a heterocyclic ring which may contain a substituent; and a hydroxyl group of a lower hydroxyalkyl group or a heterocyclic ring substituted with a hydroxyl group or a lower hydroxyalkyl group may form an ester bond with a phosphoric acid group or a salt thereof, or with an acyl group which may contain a substituent;

K ₄ means a hydrogen atom, a lower alkyl group, a phenyl group which may contain a substituent, or a benzyl group;

X is a carbon atom, CH or a nitrogen atom, provided that when A is an oxygen atom, then X cannot be a nitrogen atom); and

A, K-, K ₈ and K ₉ have the meanings defined above)] or their salts.

The present invention also relates to a medicament containing, as an active ingredient, a compound represented by formula (1a) or a salt thereof.

The present invention also relates to a pharmaceutical composition comprising a compound represented by formula (1a), or a salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to the use of a compound represented by formula (1a), or a salt thereof, for the manufacture of a medicament.

According to the present invention, the SCCR inhibitory effect of the acrylonitrile derivative or its salt can eliminate the SCCR associated resistance to the anticancer agent. In addition, the effect of the anticancer agent on cancer cells in which SCCR is expressed can be potentiated. In addition, in accordance with the present invention, the bioavailability of the anticancer agent of interest is increased, which leads to an increase in the quality of anticancer chemotherapy.

[FIG. 1] The graph shows the effect of some compounds of the present invention on the resistance of P388 / SCCR cells to §N-38.

[FIG. 2] The graph shows the effect of some compounds of the present invention to enhance the accumulation of §N-38 in K562 / SCCR cells.

Examples of an aromatic hydrocarbon group containing a fused ring which may be substituted with a halogen atom represented by Ag ² in formula (1) include C10-C14 aryl groups. Specific examples include naphthyl, anthracenyl, and phenanthryl. Examples of a halogen atom by which the aromatic hydrocarbon group Ag ² may be substituted include a fluorine atom, a chlorine atom, and an iodine atom.

Examples of lower alkyl groups represented by K ₃ , K _3a -B _{3 £} , K ₄ or K ₉ in formula (1) include linear or branched C1-C6 alkyl groups. Specific examples include methyl, ethyl, npropyl, isopropyl and n-butyl. Of these groups, methyl is particularly preferred.

Examples of lower alkoxy groups represented by K ₃ , K _3a - _{B 3 £} , K- or K ₈ include linear or branched C1-C6 alkoxy groups and C3-C6 cycloalkoxy groups. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. Of these groups, methoxy is particularly preferred.

Examples of halogen atoms include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of lower hydroxyalkyl groups represented by either K _3a - _{B 3 £} include linear or branched C1-C6 hydroxyalkyl groups. Specific examples include hydroxymethyl, hydroxyethyl and 1-hydroxypropyl. Of these groups, a hydroxymethyl group is particularly preferred.

Examples of aromatic hydrocarbon groups represented by K ₃ or K _3a - _{B 3 £} include linear or branched C6-C14 aryl groups. Specific examples include phenyl and naphthyl. Examples of the group to which the aromatic hydrocarbon group K ₃ may be substituted include an amino group and a nitro group. Specific examples include a nitrophenyl group and an aminophenyl group.

Examples of the group to which the phenyl group K4 may be substituted include halogen atoms and lower alkoxy groups. The halogen atom and lower alkoxy group have the meanings defined above with respect to K3.

Examples of lower alkyl groups which may contain substituents and which are represented by K ₅ and K ₆ include linear or branched C1-C6 alkyl groups. Examples of a group to which a lower alkyl group may be substituted include C1-C6 alkylamino groups and di (C1-C6 alkyl) amino groups. Specific examples include methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, dimethylamino and diethylamino.

The lower hydroxyalkyl group represented by K ₅ or K ₆ , and the aromatic hydrocarbon group which may contain a substituent, have the meanings defined for K3.

Examples of the heterocyclic group represented by K ₅ or K ₆ include alicyclic or aromatic heterocyclic compounds, each of which contains at least one heteroatom in the ring. Specific examples include piperazinyl, piperidino, morpholino, imidazole and pyrrolidinyl.

Examples of a heterocyclic ring which may contain a substituent and which may be formed from K ₅ or K ₆ together with an adjacent nitrogen atom include pyrrolidine, imidazole, pyridine, piperidine, pyrimidine, piperazine, morpholine, indole, benzimidazole, benzopyrazole and quinoline. Examples of a group to which said heterocyclic rings may be substituted include a hydroxyl group, lower alkyl groups and lower hydroxyalkyl groups. These groups have the meanings defined above.

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Examples of the substituent ΝΚ. ₅ (Κ. ₆ ) include an amino group, a dimethylamino group, a эт methyl ethanolamino group (- ^ CH ₃ ) СН ₂ СН ₂ ОН), a phosphate ester of Ν-methylethanolamine group (- ^ CH ₃ ) СН ₂ СН ₂ ОН) and their salt, monosuccinate Ν- methanolamino groups (-Ν (ΟΗ ₃ ) ΟΗ ₂ ΟΗ ₂ ΟΗ). pyrrolidino group, piperidino group, morpholino group, 4-hydroxypiperidino group, phosphate ester of 4-hydroxypiperidino group and its salt, monosuccinate of 4-hydroxypiperidino group, 4 methylpiperazino ethanol group, 4-ethanol piperazino-ethanol-4-ethanol group Ν'-trimethylethylenediamine group (^ CH3) CH2CH2ZHSNzD).

The hydroxy group in the lower hydroxyalkyl group represented by K ₅ or K ₆ and the hydroxy group in the hydroxyl group or lower hydroxyalkyl group with which the heterocyclic group may be substituted, the heterocyclic group formed by K ₅ or K ₆ , together with the adjacent nitrogen atom, can form an ester bond with a phosphate group or a salt thereof, or with an acyl group which may contain a substituent.

Examples of the acyl group include C1-C8 lower alkanoyl groups. Specific examples include formyl, acetyl, propionyl, malonyl and succinyl. Examples of the group to which the acyl group may be substituted include lower dialkylamino groups; phenylcarbamoyl groups which may contain a substituent, Ν-lower alkylcarbamoyl groups which may contain a substituent, Ν-Ν-lower alkylcarbamoyl groups, and Ν-heterocyclic carbamoyl groups which may be substituted by an aliphatic heterocyclic ring. The lower alkyl group is as defined above.

Examples of the group to which the phenylcarbamoyl group, the Ν-lower alkylcarbamoyl group or the Ν, Ν-di-lower alkylcarbamoyl group may be substituted include lower alkylamino groups such as methylamino group and ethylamino group; and lower dialkylamino groups such as diethylamino and dipropylamino.

Examples of a Ν-heterocyclic carbamoyl group which may be substituted with an aliphatic heterocyclic ring include Ν-piperidinocarbonyl groups, each of which is substituted with pyrrolidine, piperidine, piperazine or a similar heterocyclic ring.

Examples of the acyl group which may have a substituent include dimetilaminoatsetilnuyu group dietilaminoetilaminokarbonilpropionilnuyu group dietilaminopropilaminokarbonilpropionilnuyu group dietilaminofenilaminokarbonilpropionilnuyu group, 4-piperidinopiperidine-1-ylcarbonyl group and 4-piperidinopiperidine 1-ilkarbonilpropionilnuyu group.

The acrylonitrile derivatives of the present invention can form pharmaceutically acceptable salts of said derivatives, and such salts are included within the scope of the present invention. Examples of salts include inorganic salts such as hydrochlorides, sulfates, nitrates and phosphates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic acid salts such as p-toluenesulfonates, methanesulfonates, fumarates, succinates and lactates. The compounds of the present invention can be presented in the form of solvates (hydrates). Hydrates are also included in the scope of the present invention. Derivatives of the acrylonitrile of the present invention may include their isomers and each of such isomers and mixtures of such isomers are also included in the scope of the present invention.

Of these compounds, the following compounds and salts are most preferred: (2) -2- (3,4-dimethoxyphenyl) -3- (5-nitrothiophen-2-yl) acrylonitrile (compound 1), (2) -3- (5 -bromothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 2), (2) -3- (5-aminothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile ( compound 3), (2) -2- (3,4-dimethoxyphenyl) -3- (5-piperidin-1-ylthiophen-2-yl) acrylonitrile (compound 4) or its hydrochloric acid salt (compound 11), (2) -2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylthiophen-2-yl) acrylonitrile (compound 5), (2) -2- (3,4-dimethoxyphenyl) -3 - [5- (4-hydroxypy eridin-1-yl) thiophen-2-yl] acrylonitrile (compound 6) or its hydrochloric acid salt (compound 12), (2) -2- (3,4-dimethoxyphenyl) -3- {5 - [( 2-hydroxyethyl) methylamino] thiophen-2-yl} acrylonitrile (compound 7), (2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) thiophen-2- yl] acrylonitrile (compound 8) or its salt of hydrochloric acid (compound 13), (2) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1- yl] thiophen-2-yl} acrylonitrile (compound 9) or its hydrochloric acid salt (compound 14), its methanesulfonic acid salt (compound 59), its acid the sulfuric acid salt (compound 100), its sulfuric acid salt (compound 101) or its nitric acid salt (compound 102), (2) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2- dimethylaminoethyl) methylamino] thiophen-2-yl} acrylonitrile (compound 10) or its hydrochloric acid salt (compound 15), mono (1- {5 - [(2) -2-cyano-2- (3,4- dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) phosphate (compound 16) or its sodium salt (compound 17),

- 5 014555 mono (1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) succinate (compound 18) or its sodium salt (compound 57), (2) -2- (3,4-dimethoxyphenyl) -3- (5-nitrofuran-2-yl) acrylonitrile (compound 19), (2) -2- (3,4-dimethoxyphenyl) -3- (5-hydroxymethylfuran-2-yl) acrylonitrile (compound 20), (2) -2- (3,4-dimethoxyphenyl) -3- [5- (3-nitrophenyl) furan-2-yl] acrylonitrile ( compound 21), (2) -3- [5- (3-aminophenyl) furan-2-yl] -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 22) or its hydrochloric acid salt (compound 23) , (2) -2- (3,4-dimethoxyphenyl) -3- (5-piperidinyl-2-ylfuran-2-yl) acryl onitrile (compound 24), (2) -2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylfuran-2-yl) acrylonitrile (compound 25), (2) -2- (3, 4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) furan-2-yl] acrylonitrile (compound 26), (2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) furan-2-yl] acrylonitrile (compound

27) or its salt of hydrochloric acid (compound 29), (2) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] furan-2 -yl} acrylonitrile (compound 28) or its salt of hydrochloric acid (compound 50), (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile (compound 30), its salt of hydrochloric acid (compound 31) or a methanesulfonic acid salt thereof (compound 32),

Ν-oxide (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile (compound 33), (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-3-ylacrylonitrile (compound 34) or its hydrochloric acid salt (compound 36), (2) -2- (3,4-dimethoxyphenyl) -3- (6-methoxypyridin-3-yl) acrylonitrile (compound 35) or its hydrochloric acid salt ( compound 37), (Ζ) -2- (3,4-dimethoxyphenyl) -3-pyridin-2-ylacrylo nitrile (compound 38), ^) - 2- (3,4-dimethoxyphenyl) -3- (1H-pyrrole -2-yl) acrylonitrile (compound 39) or its salt of hydrochloric acid (compound 40),

^) - 2- (3,4-dimethoxyphenyl) -3- (3H-imidazol-4-yl) acrylonitrile (compound 41), ^) - 3- (3-benzyl-2-methylsulfanyl-3H-imidazole-4- il) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 42),

^) - 2- (3,4-dimethoxyphenyl) -3- (4-methyl-2-phenylthiazol-5-yl) acrylonitrile (compound 43), ^) - 3- (3,4-dimethoxyphenyl) -2-pyridine -3-ylacrylonitrile (compound 44) or its salt of hydrochloric acid (compound 46),

^) - 3- (3,4-dimethoxyphenyl) -2-pyridin-2-ylacrylonitrile (compound 45) or its salt of hydrochloric acid (compound 47),

^) - 2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylaminoethyl) methylamino] furan-2-yl} acrylonitrile (compound 48) or its hydrochloric acid salt (compound 49), mono (1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) succinate (compound 51) or its sodium salt (compound 58) mono (1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) phosphate (compound 52) or its sodium salt (compound 53)

^) - 3- (5-bromofuran-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 54), (E) -3- (3,4-dimethoxyphenyl) -2-thiophen-2- ilacrylonitrile (compound 55), ^) - 3- (3,4-dimethoxyphenyl) -2-thiophen-3-ylacrylonitrile (compound 56), hydrochloric acid salt 1- [5 - [^) - 2-cyano-2 - (3,4-dimethoxyphenyl) vinyl] thiophen-2yl] piperidin-4-yl-No (2-diethylaminoethyl) succinamate (compound 60), salt of hydrochloric acid 1- [5 - [^) - 2-cyano- 2- (3,4-dimethoxyphenyl) vinyl] thiophen-2yl] piperidin-4-yl-No (3-diethylaminopropyl) succinamate (compound 61), salt of p-toluenesulfonic acid 1- [5 - [^) - 2-cyano -2- (3,4-dimethoxyphenyl ) vinyl] thiophen-2yl] piperidin-4-yldimethylaminoacetate (compound 62) or its hydrochloric acid salt (compound 104), hydrochloric acid salt 1- [5 - [^) - 2-cyano-2- (3 , 4-dimethoxyphenyl) vinyl] thiophen-2yl] piperidin-4-yl [1,4 '] bipiperidinyl-1'-carboxylate (compound 63), salt of hydrochloric acid 1- [5 - [^) - 2- cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2yl] piperidin-4-yl-4- [1,4 '] bipiperidinyl-1'-yl-4-oxobutylate (compound 64),

^) - 2- (3,4-dimethoxyphenyl) -3-quinolin-4-ylacrylonitrile (compound 65), (Ζ) -3-benzo [b] thiophen-3-yl-2- (3,4-dimethoxyphenyl) acrylonitrile (compound 66), (Ζ) -2- (3,4-dimethoxyphenyl) -3- (1-methyl-1H-benzimidazol-2-yl) acrylonitrile (compound 67), (Ζ) -2- (3, 4-dimethoxyphenyl) -3- (1-methyl-1H-indol-3-yl) acrylonitrile (compound 68), (Ζ) -3-benzofuran-2-yl-2- (3,4-dimethoxyphenyl) acrylonitrile (compound 69), ^) - 3- (2-chloroquinolin-3-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 70), (E) -2-benzotriazole-1-yl-3 - (3, 4-dimethoxyphenyl) acrylonitrile (compound 71), ^) - 2-benzofuran-3-yl-3 - (3,4-dimethoxyphenyl) acrylonitrile l (compound 72) *) - 3- (2-chloro-6-methoxyquinoline-3-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (Compound 73)

- 6 014555 (E) -2-benzothiazol-2-yl-3- (3,4-dimethoxyphenyl) acrylonitrile (compound 74), (2) -3- (2,3-dihydrobenzofuran-5-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 75), (2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-fluorophenyl) isoxazol-3-yl] acrylonitrile (compound 76), ( 2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methoxyphenyl) isoxazol-3-yl] acrylonitrile (compound 77), (2) -2- (3,4-dimethoxyphenyl) -3 -quinolinyl-2-ylacrylonitrile (compound 78), (2) -3- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-2-ylacrylonitrile (compound 79), (2) -3- ( 2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-2-ylacrylonitrile (compound 80), (E) -3- (2-chloro-6-methoxy olin-3-yl) -2-thiophen-2-ylacrylonitrile (compound 81), (2) -3- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-2-ylacrylonitrile (compound 82) , (E) -2-benzotriazol-1-yl-3 - (2-chloro-6-methoxyquinolin-3-yl) acrylonitrile (compound 83), (E) -2-benzothiazol-2-yl-3- (2 -chloro-6-methoxyquinolin-3-yl) acrylonitrile (compound 84), (2) -2-pyridin-2-yl-3-quinolin-4-ylacrylonitrile (compound 85), (2) -2-pyridin-3 -yl-3-quinolin-4-ylacrylonitrile (compound 86), (E) -3-quinolin-4-yl-2-thiophen-2-ylacrylonitrile (compound 87), (2) -3-quinolin-4-yl -2-thiophen-3-ylacrylonitrile (compound 88), (E) -3-benzo [b] thiophen-3-yl-2-thiophen-2-ylacrylon tril (compound 89), (E) -3-benzo [b] thiophen-3-yl-2-benzothiazol-2-ylacrylonitrile (compound 90), (2) -3-benzofuran-2-yl-2-benzofuran- 3-yl-acrylonitrile (compound 91), (E) -2-benzothiazol-2-yl-3- (1-methyl-1H-indol-3-yl) acrylonitrile (compound 92), (2) -3- (10- chlorantracen-9-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 93), (2) -3- (3,4-dimethoxyphenyl) -3-naphthalene-2-ylacrylonitrile (compound 94), (Ζ ) -3- (3,4-dimethoxyphenyl) -3-phenanthren-9-ylacrylonitrile (compound 95), 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophene- 2-yl] piperidin-4-yldiethylaminoacetate (compound 103), its salt p-toluenesulfone howl acid (Compound 96) or its salt with hydrochloric acid (Compound 105)

1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldiethylcarbamate (compound 97), 1- [5- hydrochloric acid salt [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2yl] piperidin-4-yl-Y- (2-diethylaminoethyl) -Y-methyl succinamate (compound 98) and

1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl-Y- (4 diethylaminophenyl) succinamate (compound 99).

Derivatives of the acrylonitrile of the present invention and their salts can be obtained using, for example, the following reaction schemes (A) or (B):

Scheme (A)

A ^ CHO +

(16) (17) (1-1)

Scheme (B) + Ar'CHO ----- ► 'Chdl (18) (19) (1-2) (where Ar ¹ and Ar ² have the meanings defined above).

In particular, during the condensation reaction between aromatic aldehyde (16) or (19) and aromatic acetonitrile (17) or (18), an acrylonitrile derivative (1-1) or (1-2) can be obtained. More specifically, a condensation reaction between aromatic aldehyde (16) and 3,4-dimethoxybenzyl cyanide (17) leads to the formation of an acrylonitrile derivative (1-1), and a condensation reaction between aromatic acetonitrile (18) and 3,4-dimethoxybenzaldehyde (19) to the formation of acrylonitrile derivative (1-2).

Alternatively, an acrylonitrile derivative (1-1) can be obtained during the condensation reaction between a polycyclic aromatic aldehyde (16) and 3,4-dimethoxybenzyl cyanide (17). In the course of the condensation reaction between heterocyclic acetonitrile (18) and quinoline carboxaldehyde (19), an acrylonitrile derivative (1-2) can be obtained. Also, in the course of the condensation reaction between benzothiophenecarboxaldehyde, benzofurancarboxaldehyde or indolocarboxaldehyde (19) and heterocyclic acetonitrile (18), an acrylonitrile derivative (1-2) can be obtained.

The condensation reaction is preferably carried out in the presence of a base such as sodium alkoxide, sodium hydroxide or potassium hydroxide. In the case where sodium alkoxide is used, the condensation reaction is carried out in an alcohol solvent such as methanol or ethanol at a temperature corresponding to

- 7 014555, which approximately corresponds to the temperature of ice cooling and the boiling temperature under reflux, while in the case of sodium hydroxide, the condensation reaction is carried out in a solvent mixture comprising water and an inert solvent, such as methylene chloride or chloroform, in the presence of a quaternary ammonium salt or similar compound, added to the mixture.

Each of the acrylonitrile derivatives containing the heterocyclic ring of the present invention, or their salts can be introduced as such. Alternatively, said derivatives or salts thereof may be mixed with a pharmaceutically acceptable carrier, such as a dispersing adjuvant or excipient, and may be used in the form of injectable preparations or oral preparations such as a powder, solution, capsule, suspension, emulsion, syrup, elixir, granules, pills, tablets, lozenges or lemonade. These products can be obtained using a conventional method.

Examples of such a carrier include water-soluble monosaccharides, oligosaccharides and polysaccharides such as mannitol, lactose and dextran; gelling or water soluble celluloses, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose; cellulose water-absorbing and poorly soluble in water, such as crystalline cellulose, such as α-cellulose, cross-linked sodium carboxymethyl cellulose and its derivatives; water-absorbing and poorly water-soluble polysaccharides, such as hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin and their derivatives; water-absorbing and poorly soluble in water gums, such as gum arabic, tragacanth, glucomannan and their derivatives; crosslinked vinyl polymers such as polyvinylpyrrolidone, crosslinked polyacrylic acid and its salts, crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate and its derivatives; and lipids forming molecular aggregates (e.g. liposomes) such as phospholipid and cholesterol.

In the case where the compound of the present invention has a low solubility, said compound may be solubilized. Examples of the solubilization method include those that are generally applicable to drugs, such as a method in which a surfactant is added to the compound (for example, a polyoxyethylene alcohol ester, a polyoxyethyleneacyl ester, a sorbitanacyl ester or a polyoxyethylene sorbitanacyl ester), and a method using a water soluble polymer (e.g. polyethylene glycol). If desired, for example, a method for preparing a soluble salt of a compound or a method using the preparation of a clathrate compound based on cyclodextrin or a similar material may be used. A suitable solubilization method may be selected in accordance with the nature of the desired acrylonitrile derivative or salt thereof.

Due to the potent SCCR inhibitory effect, the compound of the present invention can be used as an agent for overcoming resistance to an anticancer agent and as an agent for potentiating the effect of an anticancer agent.

The SCCR inhibitor can be used as an agent to overcome resistance to an anticancer agent, in the case of cancer in which there is acquired SCCR-mediated resistance to an administered anti-cancer drug. In this case, the SCCR inhibitor can be used as an agent for potentiating the effect of the anticancer agent, in the case of cancer in which SCCR is expressed and low sensitivity to the anticancer drug is noted. There is no limitation on the anticancer agent that targets the agent to overcome resistance to the anticancer agent or the agent to potentiate the effect of the anticancer agent containing the SCCR inhibitor of the present invention as an active ingredient, the main thing is that the anticancer drug can serve as a substrate for SCCR or its analogue. Examples of such an anti-cancer agent include topoisomerase I inhibitors such as irinotecan hydrochloride / CPT-11 (active metabolite: §N-38) and topotecan; topoisomerase II inhibitors such as mitoxantrone, doxorubicin, daunorubicin, bisanthrene and etoposide; antifolates such as methotrexate; and therapeutic drugs acting on target molecules such as gefitinib and imatinib. It should be noted that there are no specific restrictions on the analogue of SCCR, the main thing is that it is characterized by the same resistance to the anticancer drug as SCCR.

The dose of the SCCR inhibitor of the present invention can be appropriately determined taking into account, for example, the route of administration or the patient's symptom. The daily dose for an adult is preferably from 1 mg to 10 g, more preferably from 100 mg to 10 g, and most preferably from 500 mg to 10 g. There are no particular restrictions on the ratio between the anti-cancer drug and the BCCR inhibitor, and their preferred ratio may vary, for example, depending on the type of anticancer drug or the inhibitor used. In the case where, for example, irinotecan hydrochloride is used as an anticancer drug, the mass ratio of the anticancer drug to the SCCR inhibitor is preferably 1: 1-1: 500, particularly preferably 1: 1-1: 100, and more preferably from 1: 1 to 1:10.

- 8 014555

Examples

The present invention will now be described in more detail using examples that should in no way be construed as limiting the present invention.

Example 1. Obtaining a derivative of acrylonitrile containing a heterocyclic ring (stage 1). The introduction of an amine in a halogen-containing heterocyclic aldehyde.

Water and an amine (3 eq.) Are added to the reactor in which the halogen-containing heterocyclic aldehyde is located. When refluxed, the mixture was stirred for ten minutes to one day. After cooling, the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the compound of interest.

(Production Step 2. Method A). Stage condensation reaction between aromatic or polycyclic aromatic aldehyde and 3,4-dimethoxybenzyl cyanide.

Equal amounts (in equivalents) of the aromatic or polycyclic aromatic aldehyde derivative and 3,4-dimethoxybenzyl cyanide are introduced into the reactor and ethanol is added. Next, a calcium chloride tube is connected to the reactor and the mixture in the reactor is stirred until dissolved. Separately, 1-2 equivalents of sodium ethoxide are weighed and dissolved in ethanol, then the solution is added dropwise to the above solution. The mixture is stirred at a temperature from about the temperature of cooling with ice to about the boiling point under reflux. After completion of the reaction, water was added to the reaction mixture, and ethanol was evaporated to dryness. The mixture was extracted with chloroform and the organic layer was washed with brine, then dried over anhydrous sodium sulfate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography and recrystallized from ethanol to obtain the compound of interest.

(Production Step 2: Method B). Stage condensation reaction between aromatic acetonitrile and 3,4-dimethoxybenzaldehyde.

Equal amounts (in equivalents) of the aromatic acetonitrile derivative and 3,4-dimethoxybenzaldehyde are introduced into the reactor and ethanol is added. Next, a calcium chloride tube is connected to the reactor and the mixture in the reactor is stirred until dissolved. Separately, 1-2 equivalents of sodium ethoxide are weighed and dissolved in ethanol, then the solution is added dropwise to the solution obtained above. The mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and ethanol was evaporated to dryness. The mixture was extracted with chloroform and the organic layer was washed with brine, then dried over anhydrous sodium sulfate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography and recrystallized from ethanol to obtain the compound of interest.

(Production Step 3: Method B). A condensation reaction step between heterocyclic acetonitrile and quinoline carboxaldehyde, benzothiophenecarboxaldehyde, benzofurancarboxaldehyde or indole carboxaldehyde.

Equimolar amounts of a heterocyclic acetonitrile derivative and an aldehyde derivative are introduced into the reactor. Using the methodology described in Production Step 2: Method B, a compound of interest is obtained.

The following describes specific options for methods of obtaining these derivatives and the results of their analysis.

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (5-nitrothiophen-2-yl) acrylonitrile (compound 1).

5-Nitrothiophene-2-carboxaldehyde (3.14 g) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (3.54 g) according to method A (production step 2), to obtain the desired product (yield: 540 mg, 8.5% )

Orange crystals. MS (APC1, t / ζ): 316 (M) ^- .

Ή-NMR (СОС1 ₃ ) δ: 7.93 (1Н, d,> 4.4), 7.56 (1Н, d,> 4.4), 7.43 (1Н, s), 7.30 ( 1H, dd,> 2.0, 8.3), 7.12 (1H, d,> 2.0), 6.94 (1H, d, 1 = 8.3), 3.97 (3H, s ), 3.95 (3H, s).

Preparation of (2) -3- (5-bromothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 2).

5-Bromothiophen-2-carboxaldehyde (381 mg) was subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (355 mg) according to method A (production step 2), to obtain the desired product (yield: 359 mg, 51%).

Light yellow crystals. MS (APC1, t / ζ): 349 (M) ⁺ .

Ή-NMR (COC1 ₃ ) δ: 7.41 (1H, d), 7.31 (1H, d,> 4.2), 7.21 (1H, dd,> 2.2, 8.5), 7.10 (1H, d,> 4.2), 7.08 (1H, d,> 2.2), 6.90 (1H, d, 1 = 8.5), 3.96 (3H, s ), 3.93 (3H, s).

Preparation of (2) -3- (5-aminothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 3).

Compound 1 (316 mg) was dissolved in ethanol (25 ml), and calcium chloride dihydrate (132 mg) and zinc powder (2.55 g) were added to the solution, followed by stirring for 2 hours at the boil under reflux. The reaction mixture was filtered using a loose pad of celite, which removed the zinc powder, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the desired product (yield: 35 mg,

- 9 014555

12%).

Fawn crystals. MS (Ε8Ι, t / ζ): 287 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.37 (1Н, d), 7.14 (1Н, d, 1 = 3.9), 7.13 (1Н, dd, 1 = 2.4, 8.3 ), 7.04 (1H, d, 1 = 2.4), 6.88 (1H, d, 1 = 8.3), 6.13 (1H, d, 1 = 3.9), 4.34 (2H, br s), 3.94 (3H, s), 3.91 (3H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- (5-piperidin-1-ylthiophen-2-yl) acrylonitrile (compound 4).

According to the procedure used in Production Step 1, the amino derivative obtained from piperidine (1.02 g) is introduced into 5-bromothiophen-2-carboxaldehyde (764 mg) to obtain 5-piperidin-1-ylthiophen-2-carbaldehyde (yield: 500 mg , 64%). The resulting 5-piperidin-1-ylthiophen-2-carbaldehyde (293 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (266 mg) according to method A (production step 2) to obtain the desired product (yield: 279 mg, 53%) .

Yellow crystals. MS (Ε8Ι, t / ζ): 355 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.36 (1Н, d), 7.22 (1Н, d, 1 = 4.2), 7.12 (1Н, dd, 1 = 2.2, 8.5 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.06 (1H, d, 1 = 4.2), 3.94 (3H, s), 3.90 (3H, s), 3.29-3.43 (4H, m), 1.60-1.76 (6H, m).

Obtaining ^) - 2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylthiophen-2-yl) acrylonitrile (compound 5).

According to the procedure used in the production step 1, the amino derivative obtained from morpholine (523 mg) is introduced into 5-bromothiophen-2-carboxaldehyde (382 mg) to obtain 5-morpholin-4-ylthiophen-2-carbaldehyde (yield: 176 mg, 45 %). The resulting 5-morpholin-4-ylthiophen-2-carbaldehyde (172 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (154 mg) according to method A (production step 2) to obtain the desired product (yield: 46 mg, 15%) .

Yellow crystals. MS (Ε8Ι, t / ζ.): 357 (M + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.38 (1H, d), 7.24 (1H, d, 1 = 4.4), 7.14 (1H, dd, 1 = 2.2, 8.3 ), 7.05 (1H, d, 1 = 2.2), 6.88 (1H, d, 1 = 8.3), 6.08 (1H, d, 1 = 4.4), 3.95 (3H, s), 3.91 (3H, s), 3.83-3.88 (4H, m), 3.28-3.33 (4H, m).

Obtaining ^) - 2- (3,4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) thiophen-2-yl] acrylonitrile (compound 6).

According to the procedure used in the production step 1, an amino derivative obtained from 4hydroxypiperidine (3.03 g) is introduced into 5-bromothiophen-2-carboxaldehyde (1.91 g) to obtain 5- (4hydroxypiperidin-1-yl) thiophen-2 -carbaldehyde (yield: 1.36 g, 64%). The resulting 5- (4hydroxypiperidin-1-yl) thiophene-2-carbaldehyde (1.27 g) was subjected to a condensation reaction with 3.4 dimethoxybenzyl cyanide (1.06 g) according to method A (production step 2) to obtain the desired product (yield: 1 , 09 g, 50%).

Yellow crystals. MS (Ε8Ι, t / ζ): 371 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.36 (1Н, d), 7.22 (1Н, d, 1 = 4.4), 7.13 (1Н, dd, 1 = 2.2, 8.3 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.3), 6.04 (1H, d, 1 = 4.4), 3.88 -3.98 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.60-3.67 (2H, m), 3.14-3.22 (2H , m), 1.98-2.06 (2H, m), 1.68-1.78 (2H, m).

Preparation of ^) - 2- (3,4-dimethoxyphenyl) -3- {5 - [(2-hydroxyethyl) methylamino] thiophen-2-yl} acrylonitrile (compound 7).

According to the procedure used in production step 1, an amino derivative obtained from Ν-methylethanolamine (2.25 g) is introduced into 5-bromothiophen-2-carboxaldehyde (1.91 g) to obtain 5 - [(2-hydroxyethyl) methylamino] thiophene-2-carbaldehyde (yield: 991 mg, 53%). The resulting 5 - [(2-hydroxyethyl) methylamino] thiophene-2-carbaldehyde (682 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (654 mg) according to method A (production step 2) to obtain the desired product (yield: 300 mg , 24%).

Orange crystals. MS (Ε8Ι, t / ζ): 345 (M + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.35 (1H, d), 7.21 (1H, d, 1 = 4.2), 7.12 (1H, dd, 1 = 2.2, 8.3 ), 7.03 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.3), 5.91 (1H, d, 1 = 4.2), 3.94 (3H, s), 3.92 (2H, q, 1 = 5.6), 3.90 (3H, s), 3.56 (2H, t, 1 = 5.6), 3.15 (3H c) 1.63 (1H, t, 1 = 5.6).

Obtaining ^) - 2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) thiophen-2-yl] acrylonitrile (compound 8).

According to the procedure used in the production step 1, an amino derivative obtained from 1 methylpiperazine (6.01 g) is introduced into 5-bromothiophen-2-carboxaldehyde (3.82 g) to obtain 5- (4 methylpiperazin-1-yl) thiophen-2 -carbaldehyde (yield: 3.71 g, 88%). The resulting 5- (4-methylpiperazin-1yl) thiophene-2-carbaldehyde (2.10 g) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (1.77 g) according to method A (production step 2) to obtain the desired product (yield : 2.47 g, 67%).

Yellowish-orange crystals. MS (Ε8Ι, t / ζ): 370 (M + H) ⁺ .

Я-NMR (SPS1 ₃ ) δ: 7.37 (1H, d), 7.22 (1H, d, 1 = 4.4), 7.13 (1H, dd, 1 = 2.2, 8.5 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.04 (1H, d, 1 = 4.4), 3.94 (3H, s), 3.90 (3H, s), 3.33-3.37 (4H, m), 2.53-2.58 (4H, m), 2.36 (3H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] thiophen-2-yl} acrylonitrile (compound 9).

According to the method used in stage 1, the amino derivative obtained from 1

10 014555 piperazinethanol (7.81 g), is introduced into 5-bromothiophen-2-carboxaldehyde (3.82 g) to obtain 5- [4- (2hydroxyethyl) piperazin-1-yl] thiophene-2-carbaldehyde (yield: 3.22 g, 67%). The resulting 5- [4- (2hydroxyethyl) piperazin-1-yl] thiophene-2-carbaldehyde (1.85 g) was subjected to a condensation reaction with 3.4 dimethoxybenzyl cyanide (1.37 g) according to method A (production step 2) to obtain the desired product (yield: 1.51 g, 49%).

Yellowish-orange crystals. MS (Ε8Ι, t / ζ): 400 (M + H) ⁺ .

'H-NMR (SPS1 ₃ ) δ: 7.37 (1H, d), 7.23 (1H, d, 1 = 4.4), 7.13 (1H, dd, 1 = 2.2, 8, 3), 7.05 (1H, d, 1 = 2.2), 6.88 (1H, d, 1 = 8.3), 6.05 (1H, d, 1 = 4.4), 3, 95 (3H, s), 3.91 (3H, s), 3.67 (2H, m), 3.33-3.38 (4H, m), 2.65-2.70 (4H, m) 2.60-2.65 (2H, m); 2.57 (1H, m).

Preparation of SH) -2- (3,4-dimethoxyphenyl) -3- [5 - [(2-dimethylaminoethyl) methylamino] thiophen-2-yl} acrylonitrile (compound 10).

According to the procedure used in the production step 1, an amine derivative obtained from Ν, Ν, Ν trimethylethylenediamine (6.13 g) is introduced into 5-bromothiophen-2-carboxaldehyde (3.82 g) to obtain 5 - [(2dimethylaminoethyl) methylamino] thiophene-2-carbaldehyde (yield: 3.26 g, 77%). The resulting 5 - [(2dimethylaminoethyl) methylamino] thiophene-2-carbaldehyde (2.12 g) was subjected to a condensation reaction with 3.4 dimethoxybenzyl cyanide (1.77 g) according to method A (production step 2) to obtain the desired product (yield: 1, 20 g, 32%).

Fawn oil.

MS (Ε8Ι, t / ζ): 372 (M + H) ⁺ .

^! H-NMR (COC1 ₃ ) δ: 7.34 (1H, d), 7.22 (1H, d, 1 = 4.2), 7.11 (1H, dd, 1 = 2.2, 8.3 ), 7.03 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.3), 5.86 (1H, d, 1 = 4.2), 3.94 (3H, s), 3.90 (3H, s), 3.48 (2H, t, 1 = 7.1), 3.10 (3H, s), 2.56 (2H, t, 1 = 7 , 1), 2.30 (6H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- (5-piperidin-1-ylthiophen-2-yl) acrylonitrile hydrochloride (compound 11).

0.1n Hydrochloric acid (7.0 ml) was added to compound 4 (226 mg) and purified water (30 ml), acetonitrile (30 ml) and chloroform (3 ml) were added to the resulting mixture to dissolve the mixture. The solution was stirred at room temperature for 1 h and the solvent was evaporated to dryness. The residue was suspended in hexane-ethyl acetate, and the solvent was evaporated to dryness, followed by thorough drying to obtain the desired product (yield: 235 mg, 94%).

Yellow crystals. MS (Ε8Ι, t / ζ): 355 (M-HC1 + H) ⁺ .

^! H-NMR (SPS1 ₃ ) δ: 7.37 (1H, s), 7.23 (1H, br.s), 7.13 (1H, dd, 1 = 2.0, 8.5), 7, 04 (1H, d, 1 = 2.0), 6.87 (1H, d, 1 = 8.5), 6.15 (1H, br.s), 3.94 (3H, s), 3, 90 (3H, s), 3.30-3.37 (4H, m), 1.72-1.80 (4H, m), 1.60-1.68 (2H, m).

Preparation of Shch) -2- (3,4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) thiophen-2yl] acrylonitrile hydrochloride (compound 12).

0.1n hydrochloric acid (3.0 ml) was added to compound 6 (100 mg) and purified water (5 ml), acetonitrile (30 ml) and chloroform (5 ml) were added to the resulting mixture to dissolve the mixture. The solution was stirred at room temperature for 1 h and the solvent was evaporated to dryness, followed by thorough drying, to obtain the desired product (yield: 95 mg, 87%).

Yellowish-orange powder. MS (Ε8Ι, t / ζ): 371 (M-HC1 + H) ⁺ .

Я-NMR (DMSO-b ₆ ) δ: 8.32 (1H, s), 7.89 (1H, s), 7.40 (1H, d, 1 = 4.4), 7.16 (1H, d, 1 = 2.0), 7.08 (1H, dd, 1 = 2.0, 8.5), 7.00 (1H, d, 1 = 8.5), 6.25 (1H, d , 1 = 4.4), 4.82 (1H, d, 1 = 3.9), 3.83 (3H, s), 3.77 (3H, s), 3.68-3.78 (1H , m), 3.50-3.60 (2H, m), 3.08-3.18 (2H, m), 1.80-1.90 (2H, m), 1.45-1.57 (2H, m).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) thiophen-2yl] acrylonitrile hydrochloride (compound 13).

0.1n Hydrochloric acid (14.9 ml) was added to compound 8 (500 mg) to dissolve, and purified water (10 ml) was added to the resulting solution, followed by stirring at room temperature for 1 h. The reaction mixture was lyophilized to obtain the desired product (yield: 546 mg, 99%).

Yellowish-orange powder. MS (Ε8Ι, t / ζ): 370 (M-HC1 + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.38 (1H, d), 7.21 (1H, d, 1 = 4.1), 7.16 (1H, dd, 1 = 2.2, 8.3 ), 7.05 (1H, d, 1 = 2.2), 6.89 (1H, d, 1 = 8.3), 6.16 (1H, d, 1 = 4.1), 3.95 (3H, s), 3.92 (3H, s), 3.86-4.00 (2H, m), 3.65-3.78 (2H, m), 3.48-3.60 (2H , m), 2.98-3.11 (2H, m), 2.86 (3H, s).

Preparation of Shch) -2- (3,4-dimethoxyphenyl) -3- [5- [4- (2-hydroxyethyl) piperazin-1yl) thiophen-2-yl} acrylonitrile hydrochloride (compound 14).

0.1n Hydrochloric acid (13.8 ml) was added to compound 9 (500 mg) to dissolve, and purified water (10 ml) was added to the resulting solution, followed by stirring at room temperature for 1 h. The reaction mixture was lyophilized to obtain the desired product (yield: 540 mg, 99%).

Yellowish-orange powder. MS (Ε8Ι, t / ζ): 400 (M-HC1 + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.39 (1Н, d), 7.22 (1Н, d, 1 = 4.1), 7.16 (1Н, dd, 1 = 2.2, 8.3 ), 7.05 (1H, d, 1 = 2.2), 6.89 (1H, d, 1 = 8.3), 6.16 (1H, d, 1 = 4.2), 4.05 -4.15 (2H, m), 3.95 (3H, s), 3.92 (3H, s), 3.90-4.05 (2H, m), 3.65-3.83

- 11 014555 (4H, m), 3.05-3.25 (4H, m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylaminoethyl) methylamino] thiophen-2-yl} acrylonitrile hydrochloride (compound 15).

0.1n Hydrochloric acid (3.8 ml) was added to compound 10 (100 mg), and purified water (5 ml) and acetonitrile (5 ml) were added to this mixture to dissolve the mixture. The specified solution was stirred at room temperature for 1 h and the solvent was evaporated to dryness, followed by thorough drying, to obtain the desired product (yield: 100 mg, 91%).

Orange powder. MS (Ε8Ι, t / ζ): 372 (M-HC1 + H) ⁺ .

Я-NMR (SBS _{1 3} ) δ: 7.38 (1Н, d), 7.21 (1Н, d, 1 = 4.1), 7.13 (1Н, dd, 1 = 2.2, 8.3 ), 7.03 (1H, d, 1 = 2.2), 6.88 (1H, d, 1 = 8.3), 6.09 (1H, d, 1 = 4.1), 4.00 -4.06 (2H, m), 3.95 (3H, s), 3.91 (3H, s), 3.24-3.30 (2H, m), 3.18 (3H, s), 2.90 (3H, s); 2.88 (3H, s).

Preparation of Mono (1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) phosphate (compound 16).

Compound 6 (400 mg) and bis (2,2,2-trichloroethyl) phosphorochloridate (1.64 g) were dissolved in pyridine (4 ml) and the resulting solution was stirred at room temperature for 2 hours. After completion of the reaction, was added to the reaction mixture methanol, followed by stirring for 30 minutes. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 7: 13) to obtain 1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2 -yl} piperidin-4-yl-bis- (2,2,2-trichloroethyl) phosphate (yield: 694 mg, 90%).

The resulting 1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl-bis (2,2,2-trichloroethyl) phosphate ( 385 mg) was dissolved in a solvent mixture (5 ml) containing pyridine and acetic acid (4: 1). To the solution was added zinc powder (353 mg) and then stirred at room temperature for 4 hours. Insoluble zinc powder was removed by filtration and the filtrate added to the resin 1KS748 (IN ₄ ⁺⁾ (11 g), followed by stirring at room temperature for 30 min The gummy material was removed by filtration and the solvent was evaporated to dryness. The residue was washed with ethanol to obtain the desired product (yield: 195 mg, 80%).

Fawn powder. MS (Ε8Ι, t / ζ): 449 (M-H) ^- .

Я-NMR (DMSO) δ: 1.71-1.77 (2H, m), 1.96-1.99 (2H, m), 3.23-3.28 (2H, m), 3.50 -3.56 (2H, m), 3.77 (3H, s), 3.83 (3H, s), 4.27-4.30 (1H, m), 6.28 (1H, d, 1 = 3.9), 7.01 (1H, d, 1 = 8.8), 7.08 (1H, dd, 1 = 2.0, 8.3), 7.16 (1H, d, 1 = 2.0), 7.91 (1H, s), 8.58 (1H, d, 1 = 3.9).

Preparation of Mono (1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) phosphate sodium salt (compound 17).

Purified water (10 ml) was added to compound 16 (100 mg) to form a suspension. Resin 1KS748 (Ia) (2 g) was added to the suspension, followed by stirring at room temperature. After the starting materials were dissolved, the gummy substance was removed by filtration and the solvent was evaporated under reduced pressure to obtain the desired product (yield: 104 mg, 95%).

Fawn powder. MS (Ε8Ι, t / ζ): 449 (M-2Ia + H) ⁺ .

Ή-NMR (ϋ ₂ Ο) δ: 7.13 (1H, s), 6.90 (1H, d, 1 = 2.2), 6.60-6.75 (3H, m), 5.96 (1H, d, 1 = 4.1), 4.05-4.08 (1H, m), 3.64 (3H, s), 3.63 (3H, s), 3.42-3.45 (2H, m), 2.69-3.01 (2H, m), 1.91-1.92 (2H, m), 1.57-1.59 (2H, m).

Preparation of Mono (1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) succinate (compound 18).

Compound 6 (200 mg) was dissolved in pyridine (2 ml), and succinic anhydride (270 mg) was added to the solution, followed by stirring under reflux for 2 hours. After completion of the reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes. The solvent was evaporated to dryness and the residue was extracted with chloroform and purified water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was washed with hexane to obtain the desired product (yield: 212 mg, 95%).

Yellow powder. MS (Ε8Ι, t / ζ): 469 (M-H) ^- .

Я-NMR (SBS _{1 3} ) δ: 7.36 (1Н, d), 7.22 (1Н, d, 1 = 4.1), 7.13 (1Н, dd, 1 = 2.2, 8.5 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.05 (1H, d, 1 = 4.1), 5.02 -5.04 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.50-3.55 (2H, m), 3.25-3.32 (2H , m), 2.69-2.72 (2Н, m), 2.64-2.67 (2Н, m), 2.00-2.05 (2Н, m), 1.83-1.89 (2H, m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (5-nitrofuran-2-yl) acrylonitrile (compound 19).

5-Nitro-2-furaldehyde (1.41 g) undergoes condensation reactions with 3,4-dimethoxybenzyl cyanide (1.77 g) according to method A (production step 2) to obtain the desired product (yield: 88 mg, 2.9% )

Orange crystals. MS (LRS'R t / ζ): 300 (M) ^- .

Ή-NMR (СОС1 ₃ ) δ: 7.53 (1Н, d, 1 = 3.9), 7.46 (1Н, d, 1 = 3.9), 7.36 (1Н, s), 7, 32 (1H, dd, 1 = 2.4, 8.3), 7.13 (1H, d, 1 = 2.4), 6.95 (1H, d, 1 = 8.3), 3.97 (3H, s), 3.95 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (5-hydroxymethylfuran-2-yl) acrylonitrile (compound

twenty).

5-Acetoxymethyl-2-furaldehyde (505 mg) undergoes condensation reactions with 3,4dimethoxybenzyl cyanide (532 mg) according to method A (production step 2) to obtain the desired product

- 12 014555 (yield: 726 mg, 85%).

Orange crystals. MS (E§1, t / ζ): 284 (M-H) ^- .

Я-NMR (СОС1 ₃ ) δ: 7.26 (1Н, s), 7.22 (1Н, dd, 1 = 2.4, 8.5), 7.12 (1Н, d, 1 = 3.7 ), 7.09 (1H, d, 1 = 2.4), 6.91 (1H, d, 1 = 8.5), 6.48 (1H, d, 1 = 3.7), 4.49 (2H, d, 1 = 6.3), 3.85 (3H, s), 3.80 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- [5- (3-nitrophenyl) furan-2-yl] acrylonitrile (compound

21).

5- (3-nitrophenyl) furfural (1.09 g) undergoes a condensation reaction with 3,4-dimethoxybenzyl cyanide (889 mg) according to method A (production step 2) to obtain the desired product (yield: 1.85 g, 98%) .

Yellowish-orange crystals. MS (APC1, t / ζ): 376 (M) ^- .

Я-NMR (CBC1 ₃ ) δ: 8.61 (1H, t, 1 = 2.0), 8.17 (1H, dd, 1 = 2.0, 8.1), 8.16 (1H, dd , 1 = 2.0, 8.1), 7.64 (1H, t, 1 = 8.1), 7.31 (1H, s), 7.30 (1H, dd, 1 = 2.2, 8.5), 7.16 (1H, d, 1 = 3.7), 7.15 (1H, d, 1 = 2.2), 7.00 (1H, d, 1 = 3.7), 6.94 (1H, d, 1 = 8.5), 3.99 (3H, s), 3.94 (3H, s).

Preparation of (Ζ) -3- [5- (3-aminophenyl) furan-2-yl] -2- (3,4-dimethoxyphenyl) acrylonitrile (compound

22).

Acetic acid (300 ml) was added to compound 21 (1.00 g) to form a suspension. Zinc powder (3.47 g) was added to the suspension, followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through a loose layer of celite and the loose layer of celite was washed with chloroform. The filtrate (acetic acid-chloroform solution) was evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the desired product (yield: 184 mg, 24%).

Yellow crystals. MS (E1, t / z): 347 (M + H) ⁺ .

Я-NMR (SPS1 ₃ ) δ: 7.24-7.28 (2H, m), 7.18-7.23 (3H, m), 7.14 (1H, d, 1 = 2.4), 7.08 (1H, d, 1 = 3.9), 6.92 (1H, d, 1 = 8.8), 6.79 (1H, d, 1 = 3.9), 6.65-6 68 (1H, m), 3.97 (3H, s), 3.93 (3H, s).

Preparation of ^) - 3- [5- (3-aminophenyl) furan-2-yl] -2- (3,4-dimethoxyphenyl) acrylonitrile hydrochloride (compound 23).

0.1n Hydrochloric acid (3.7 ml) was added to compound 22 (117 mg), and purified water (30 ml), acetonitrile (30 ml) and chloroform (5 ml) were added to the resulting mixture to dissolve the mixture. The resulting solution was stirred at room temperature for 1 h and the solvent was evaporated to dryness. The residue was suspended in hexane-ethyl acetate, and the solvent was evaporated to dryness, followed by thorough drying to obtain the desired product (yield: 124 mg, 96%).

Fawn powder. MS (E§1, t / ζ): 347 (M-HC1 + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 7.88 (1H, s), 7.75 (1H, br.s.d, 1 = 7.9), 7.63 (1H, br.s), 7, 53 (1H, t, 1 = 7.9), 7.35 (1H, d, 1 = 2.2), 7.22-7.28 (3H, m), 7.17 (1H, d, 1 = 3.7), 7.09 (1H, d, 1 = 8.8), 3.87 (3H, s), 3.82 (3H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- (5-piperidin-1-ylfuran-2-yl) acrylonitrile (compound 24).

According to the method used in stage 1, the amino derivative obtained from piperidine (1.28 g) is introduced into 5-bromo-2-furaldehyde (875 mg) to obtain 5-piperidin-1-ylfuran-2-carbaldehyde (yield: 650 mg, 73%). The resulting 5-piperidin-1-ylfuran-2-carbaldehyde (179 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (177 mg) according to method A (production step 2) to obtain the desired product (yield: 100 mg, 30%) .

Orange crystals. MS (E1, t / z): 339 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 7.13 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.94 (1Н, s ), 6.87 (1H, d, 1 = 8.5), 6.84 (1H, d, 1 = 3.4), 5.24 (1H, d, 1 = 3.4), 3.94 (3H, s), 3.90 (3H, s), 3.37-3.42 (4H, m), 1.61-1.72 (6H, m).

Preparation of ^) - 2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylfuran-2-yl) acrylonitrile (compound 25).

According to the procedure used in Production Step 1, an amine derivative obtained from morpholine (523 mg) is introduced into 5-bromo-2-furaldehyde (350 mg) to obtain 5-morpholin-4-ylfuran-2-carbaldehyde (yield: 138 mg , 38%). The resulting 5-morpholin-4-ylfuran-2-carbaldehyde (137 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (135 mg) according to method A (production step 2) to obtain the desired product (yield: 102 mg, 40%) .

Yellow crystals. MS (E§1, t / z): 341 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.14 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.96 (1Н, s ), 6.88 (1H, d, 1 = 8.5), 6.82 (1H, d, 1 = 3.7), 5.29 (1H, d, 1 = 3.7), 3.94 (3H, s), 3.91 (3H, s), 3.82-3.86 (4H, M), 3.37-3.42 (4H, M).

Preparation of ^) - 2- (3,4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) furan-2-yl) acrylonitrile (compound 26).

According to the procedure used in Production Step 1, an amino derivative derived from 4-hydroxypiperidine (1.52 g) is introduced into 5-bromo-2-furaldehyde (875 mg) to obtain 5- (4-hydroxypiperidin-1yl) furan-2 β-carbaldehyde (yield: 660 mg, 68%). The obtained 5- (4-hydroxypiperidin-1-yl) furan-2carbaldehyde (390 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (354 mg) according to method A (production step 2) to obtain the desired product (yield: 458 mg, 65%).

Orange crystals. MS (E1, t / z): 355 (M + H) ⁺ .

- 13 014555

Я-NMR (СОС1 ₃ ) δ: 7.13 (1Н, dd, 1 = 2.2, 8.3), 7.05 (1Н, D, 1 = 2.2), 6.94 (1Н, s ), 6.87 (1H, d, 1 = 8.3), 6.83 (1H, d, 1 = 3.7), 5.28 (1H, d, 1 = 3.7), 3.88 -3.96 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.77-3.82 (2H, m), 3.15-3.23 (2H , m), 1.97-2.05 (2H, m), 1.63-1.73 (2H, m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperisin-1-yl) furan-2-yl) acrylonitrile (compound 27).

According to the procedure used in the production step 1, an amino derivative obtained from 1-methylpiperazine (1.03 g) is introduced into 5-bromo-2-furaldehyde (602 mg) to obtain 5- (4-methylpiperazin-1yl) furan-2 β-carbaldehyde (yield: 447 mg, 67%). The resulting 5- (4-methylpiperazin-1-yl) furan-2carbaldehyde (388 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (355 mg) according to method A (production step 2) to obtain the desired product (yield: 215 mg, thirty%).

Yellow crystals. MS (E§1, t / ζ): 354 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.14 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.95 (1Н, s ), 6.87 (1H, d, 1 = 8.5), 6.83 (1H, d, 1 = 3.7), 5.28 (1H, d, 1 = 3.7), 3.94 (3H, s), 3.90 (3H, s), 3.41-3.48 (4H, m), 2.50-2.56 (4H, m), 2.35 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- [5- [4- (2-hydroxyethyl) piperazin-1-yl] furan-2-yl} acrylonitrile (compound 28).

According to the procedure used in Production Step 1, an amino derivative obtained from 1-piperazine ethanol (3.91 g) is introduced into 5-bromo-2-furaldehyde (1.75 g) to obtain 5 - [(4- (2-hydroxyethyl) ) piperazin-1-yl) furan-2-carbaldehyde (yield: 1.37, 61%). The resulting 5 - [(4- (2-hydroxyethyl) piperazin-1yl) furan-2-carbaldehyde (1.12 g) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (888 mg) according to method A (production step 2) to obtain target product (yield: 1.32 g, 69%).

Fawn oil. MS (E1, t / z): 384 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.14 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.96 (1Н, s ), 6.87 (1H, d, 1 = 8.5), 6.82 (1H, d, 1 = 3.7), 5.28 (1H, d, 1 = 3.7), 3.94 (3H, s), 3.90 (3H, s), 3.63-3.69 (2H, m), 3.42-3.48 (4H, m), 2.58-2.68 (6H , m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) furan-2-yl] acrylonitrile hydrochloride (compound 29).

0.1n Hydrochloric acid (3.1 ml) was added to compound 27 (100 mg) to dissolve, and purified water (5 ml) was added to the resulting solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was lyophilized to afford the desired product (yield: 109 mg, 99%).

Fawn powder. MS (E§1, t / ζ): 354 (M-HC1 + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.16 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.98 (1Н, s ), 6.89 (1H, d, 1 = 8.5), 6.77 (1H, d, 1 = 3.7), 5.41 (1H, d, 1 = 3.7), 3.94 (3H, s), 3.91 (3H, s), 3.85-3.95 (4H, m), 3.50-3.58 (2H, m), 2.97-3.08 (2H , m) 2.86 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridyl-4-ylacrylonitrile (compound 30).

4-Pyridinecarboxaldehyde (2.14 g) was subjected to a condensation reaction with 3,4-dimethoxybenzylanilide (3.54 g) according to method A (production step 2) to obtain the desired product (yield: 3.36 g, 63%).

Light yellow crystals. MS (E§1, t / ζ): 267 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.73 (2Н, d, 1 = 6.3), 7.69 (2Н, d, 1 = 6.3), 7.36 (1Н, s), 7, 31 (1H, dd, 1 = 2.4, 8.8), 7.17 (1H, d, 1 = 2.4), 6.95 (1H, d, 1 = 8.8), 3.97 (3H, s), 3.95 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile hydrochloride (compound 31).

0.1n Hydrochloric acid (12.4 ml) was added to compound 30 (300 mg), and purified water (25 ml) and acetonitrile (20 ml) were added to the resulting mixture to dissolve the mixture. The resulting solution was stirred in the dark at room temperature for 4 hours, and the solvent was evaporated to dryness. The residue was suspended in hexane-ethyl acetate, and the solvent was evaporated to dryness, followed by thorough drying to obtain the desired product (yield: 333 mg, 98%).

Yellowish-orange powder. MS (E§1, t / ζ): 267 (M-HC1 + H) ⁺ .

Я-NMR (DMSO-b ₆ ) δ: 8.94 (2H, d, 1 = 5.4), 8.20 (3H, br.s), 7.46 (1H, d, 1 = 2.2 ), 7.39 (1H, dd, 1 = 2.2, 8.5), 7.15 (1H, d, 1 = 8.5), 3.88 (3H, s), 3.85 (3H , from).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile methanesulfonate (compound 32).

An aqueous solution of methanesulfonic acid, 0.1 mol / L (10.0 ml), was added to compound 30 (266 mg) and purified water (10 ml) and acetonitrile (5 ml) were added to the resulting solution to dissolve the mixture. The resulting solution was stirred in the dark at room temperature for 3 hours, and the solvent was evaporated to dryness. The residue was suspended in methanol and the solvent was evaporated to dryness, followed by thorough drying, to obtain the desired product (yield: 350 mg, 97%).

Yellowish-orange crystals. MS (E§1, t / ζ): 267 (M-CH ₃ §O ₃ H + H) ⁺ .

Я-NMR (DMSO-b ₆ ) δ: 9.01 (2H, d, 1 = 6.8), 8.35 (2H, d, 1 = 6.8), 8.22 (1H, s), 7.45 (1H, d, 1 = 2.0), 7.39 (1H, dd, 1 = 2.0, 8.3), 7.14 (1H, d, 1 = 8.3), 3 87 (3H, s); 3.83 (3H, s); 2.40 (3H, s).

- 14 014555

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile Ν-oxide (compound 33).

Compound 30 (266 mg) was dissolved in anhydrous dichloromethane (50 ml). To the resulting solution, m-chloroperoxybenzoic acid (266 mg) was added dropwise with stirring in an ice bath. The mixture is stirred for 15 minutes in an argon atmosphere, which is introduced from a cylinder filled with argon. The mixture was then brought back to room temperature and then stirred for about 3 hours. The reaction mixture was extracted with purified water and chloroform. The organic layer was washed with brine and the washed organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the desired product (yield: 265 mg, 94%).

Yellow crystals. MS (E1, t / z): 283 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 8.23 (2Н, d, 1 = 7.3), 7.79 (2Н, d, 1 = 7.3), 7.29 (1Н, dd, 1 = 2 4, 8.3), 7.26 (1H, s), 7.13 (1H, d, 1 = 2.4), 6.94 (1H, d, 1 = 8.3), 3.97 (3H, s), 3.95 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-3-ylacrylonitrile (compound 34).

3-Pyridinecarboxaldehyde (2.14 g) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (3.54 g) according to method A (production step 2) to obtain the desired product (yield: 4.79 g, 90%).

Light yellow crystals. MS (E§1, t / ζ): 267 (M + H) ⁺ .

Ή-NMR (ΟΌΟ1 ₃ ) δ: 8.83 (1H, d, 1 = 2.4), 8.64 (1H, dd, 1 = 1.5, 4.9), 8.44-8.48 (1H, m), 7.40-7.45 (2H, m), 7.30 (1H, dd, 1 = 2.0, 8.3), 7.16 (1H, d, 1 = 2, 0), 6.94 (1H, d, 1 = 8.3), 3.98 (3H, s), 3.95 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (6-methoxypyridin-3-yl) acrylonitrile (compound 35).

6-Methoxy-3-pyridinecarboxaldehyde (411 mg) was subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (532 mg) according to method A (production step 2) to obtain the desired product (yield: 850 mg, 96%).

Light yellow crystals. MS (E§1, t / ζ): 267 (M + H) ⁺ .

Ή-NMR (ΟΌΟ1 ₃ ) δ: 8.40-8.45 (1H, m), 8.42 (1H, s), 7.34 (1H, s), 7.25 (1H, dd, 1 = 2.2, 8.5), 7.13 (1H, d, 1 = 2.2), 6.92 (1H, d, 1 = 8.5), 6.85 (1H, m), 4, 00 (3H, s), 3.97 (3H, s), 3.93 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-3-ylacrylonitrile hydrochloride (compound 36).

0.1n Hydrochloric acid (21.0 ml) was added to compound 34 (500 mg), and purified water (40 ml), acetonitrile (50 ml) and chloroform (1 ml) were added to the mixture to dissolve the mixture. The resulting solution was stirred in the dark at room temperature for 3 hours, and the solvent was evaporated to dryness. The precipitated crystals are dried thoroughly to obtain the desired product (yield: 550 mg, 97%).

Yellow crystals. MS (E§1, t / ζ): 267 (M-HC1 + H) ⁺ .

Ή-NMR (DMSO-b) δ: 9.12 (1H, br.s), 8.80 (1H, br.s, 1 = 4.8), 8.65 (1H, br.s, 1 = 8.3), 8.14 (1H, d), 7.88 (1H, m), 7.40 (1H, d, 1 = 2.4), 7.32 (1H, dd, 1 = 2, 4, 8.5), 7.13 (1H, d, 1 = 8.8), 3.88 (3H, s), 3.83 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (6-methoxypyridin-3-yl) acrylonitrile hydrochloride (compound 37).

0.1n Hydrochloric acid (2.0 ml) was added to compound 35 (50 mg), and purified water (8 ml) and acetonitrile (8 ml) were added to the resulting mixture to dissolve the mixture. The resulting solution was stirred in the dark at room temperature for 4 hours, and the solvent was evaporated to dryness.

The precipitated crystals are dried thoroughly to obtain the desired product (yield: 55 mg, 98%).

Yellow crystals. MS (E§1, t / ζ): 297 (M-HC1 + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 8.63 (1H, d, 1 = 2.4), 8.35 (1H, dd, 1 = 2.4, 8.8), 7.33 (1H d, 1 = 2.2), 7.25 (1H, dd, 1 = 2.2, 8.5), 7.08 (1H, d, 1 = 8.5), 7.02 (1H, d, 1 = 8.8), 3.93 (3H, s), 3.86 (3H, s), 3.81 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-2-ylacrylonitrile (compound 38).

2-Pyridinecarboxaldehyde (2.14 g) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (3.54 g) according to method A (production step 2) to obtain the desired product (yield: 3.77 g, 71%).

Light yellow crystals. MS (E§1, t / ζ): 267 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.73-8.77 (1Н, m), 8.01 (1Н, d, 1 = 8.3), 7.81 (1Н, m), 7.57 ( 1H, s), 7.36 (1H, dd, 1 = 2.2, 8.5), 7.31 (1H, dd, 1 = 4.9, 7.8), 7.23 (1H, d , 1 = 2.4), 6.94 (1H, d, 1 = 8.3), 3.96 (3H, s), 3.94 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (1H-pyrrol-2-yl) acrylonitrile (compound 39).

Pyrrole-2-carboxaldehyde (951 mg) was dissolved in dichloromethane (50 ml) and ditret-butyl dicarbonate (2.40 g), 4-dimethoxyaminopyridine (61 mg) and triethylamine (1.01 g) were added to the solution, then the resulting mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (chloroform) to obtain tert-butyl 2-formylpyrrole-1-carboxylate (yield: 1.95 g, about 100%). The obtained tert-butyl-2-formylpyrrole-1-carboxylate (976 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (886 mg) according to method A (production step 2) to obtain the desired product (yield: 300 mg,

- 15 014555

24%).

Yellow powder. MS (Ε8Ι, t / ζ): 253 (M-H) ^- .

^! H-NMR (ATP1 ₃ ) δ: 9.74 (1H, br s), 7.28 (1H, s), 7.15 (1H, dd, 1 = 2.2, 8.3), 7, 05 (2H, m), 6.90 (1H, d, 1 = 8.3), 6.63-6.68 (1H, m), 6.32-6.36 (1H, m), 3, 95 (3H, s), 3.92 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (1H-pyrrol-2-yl) acrylonitrile hydrochloride (compound 40).

0.1n Hydrochloric acid (4.3 ml) was added to compound 39 (100 mg), and acetonitrile (20 ml) was added to the mixture to dissolve the mixture. The resulting solution was stirred in the dark at room temperature for 2.5 hours, and the solvent was evaporated to dryness. The precipitated crystals are dried thoroughly to obtain the desired product (yield: 100 mg, 88%).

Yellow powder. MS (Ε8Ι, t / ζ): 253 (M-HC1 + H) ⁺ .

^! H-NMR (DMSO-b ₆ ) δ: 11.38 (1H, br.s), 7.63 (1H, s), 7.02-7.17 (5H, m), 6.28-6, 32 (1H, m), 3.83 (3H, s), 3.79 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (3H-imidazol-4-yl) acrylonitrile (compound 41).

4 (5) -imidazolecarboxaldehyde (285 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (532 mg) according to method A (production step 2) to obtain the desired product (yield: 75 g, 10%).

Light yellow powder. MS (Ε8Ι, t / ζ): 256 (M + H) ⁺ .

^! H-NMR (DMSO-b ₆ ) δ: 12.5 (1H, br.s), 7.86 (1H, s), 7.75 (1H, d, 1 = 3.9), 7.25 ( 1H, d, 1 = 2.2), 7.18 (1H, dd, 1 = 2.2, 8.5), 7.04 (1H, d, 1 = 8.5), 3.84 (3H s) 3.79 (3H, s).

Preparation of (2) -3- (3-benzyl-2-methylsulfanyl-3H-imidazol-4-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 42).

1- Benzyl-2- (methylsulfanyl) -1H-imidazole-5-carbaldehyde (465 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (354 mg) according to method A (production step 2) to obtain the desired product (yield: 723 mg, 92%).

Yellow powder. MS (Ε8Ι, t / ζ): 392 (M + H) ⁺ .

^! H-NMR (CBC1 ₃ ) δ: 8.24 (1H, s), 7.40-7.30 (3H, m), 7.14-7.10 (2H, m), 6.99 (1H, dd, 1 = 2.2, 8.5), 6.94 (1H, d, 1 = 1.0), 6.83 (1H, d, 1 = 8.5), 6.78 (1H, d , 1 = 2.2), 5.23 (2H, s), 3.89 (3H, s), 3.84 (3H, s), 2.72 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (4-methyl-2-phenylthiazol-5-yl) acrylonitrile (compound 43).

4-Methyl-2-phenyl-1,3-thiazole-5-carbaldehyde (407 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (354 mg) according to method A (production step 2) to obtain the desired product (yield: 667 mg, 92%).

Yellow powder. MS (Ε8Ι, t / ζ): 363 (M + H) ⁺ .

^! H-NMR (CBC1 ₃ ) δ: 8.06-8.00 (2H, m), 7.56 (1H, s), 7.49-7.44 (3H, m), 7.25 (1H, dd, 1 = 2.2, 8.5), 7.13 (1H, d, 1 = 2.2), 6.93 (1H, d, 1 = 8.5), 3.97 (3H, s ), 3.94 (3H, s), 2.65 (3H, s).

Preparation of (2) -3- (3,4-dimethoxyphenyl) -2-pyridin-3-ylacrylonitrile (compound 44).

3-Pyridineacetonitrile (1.18 g) was subjected to a condensation reaction with 3,4-dimethoxybenzaldehyde (1.66 g) according to method B (production step 2) to obtain the desired product (yield: 1.96 g, 74%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 267 (M + H) ⁺ .

^! H-NMR (CBC1 ₃ ) δ: 8.91 (1H, d, 1 = 2.7), 8.61 (1H, dd, 1 = 1.5, 4.9), 7.92-7.97 (1H, m), 7.74 (1H, d, 1 = 2.2), 7.49 (1H, s), 7.36-7.41 (2H, m), 6.95 (1H, d , 1 = 8.5), 3.98 (3H, s), 3.96 (3H, s).

Preparation of (2) -3- (3,4-dimethoxyphenyl) -2-pyridin-2-ylacrylonitrile (compound 45).

2- Pyridineacetonitrile (1.18 g) was subjected to a condensation reaction with 3,4-dimethoxybenzaldehyde (1.66 g) according to method B (production step 2) to obtain the desired product (yield: 2.06 mg, 77%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 267 (M + H) ⁺ .

^! H-NMR (SPS1 ₃ ) δ: 8.61-8.65 (1H, m), 8.41 (1H, s), 7.73-7.81 (3H, m), 7.52 (1H, dd, 1 = 2.1, 8.3), 7.28 (1H, m), 6.96 (1H, d, 1 = 8.3), 3.98 (3H, s), 3.96 ( 3H, s).

Preparation of (2) -3- (3,4-dimethoxyphenyl) -2-pyridin-3-ylacrylonitrile hydrochloride (compound

46).

0.1n hydrochloric acid (8.3 ml) was added to compound 44 (200 mg) to dissolve, and purified water (5 ml) was added to the mixture, followed by stirring at room temperature for 20 minutes. The reaction mixture was lyophilized to afford the desired product (yield: 224 mg, 99%).

Yellow powder. MS (Ε8Ι, t / ζ): 267 (M-HC1 + H) ⁺ .

^! H-NMR (DMSO-b ₆ ) δ: 9.04 (1H, d, 1 = 1.7), 8.71 (1H, dd, 1 = 1.5, 5.1), 8.33-8 , 38 (1H, m), 8.16 (1H, s), 7.76 (1H, dd, 1 = 5.1, 8.1), 7.70 (1H, d, 1 = 2.2) 7.60 (1H, dd, 1 = 2.2, 8.5), 7.17 (1H, d, 1 = 8.5), 3.85 (3H, s), 3.82 (3H, from).

Preparation of (2) -3- (3,4-dimethoxyphenyl) -2-pyridin-2-ylacrylonitrile hydrochloride (compound

47).

0.1n Hydrochloric acid (4.1 ml) was added to compound 45 (100 mg), and acetonitrile (20 ml) was added to the mixture to dissolve the mixture. The solution was stirred in the dark at room temperature.

- 16 014555 temperature for 1 h and the solvent is evaporated to dryness. The precipitated crystals are dried thoroughly to obtain the desired product (yield: 112 mg, 99%).

Yellow crystals. MS (Ε8Ι, t / ζ): 267 (M-HC1 + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 8.63-8.67 (1H, m), 8.41 (1H, s), 7.92-7.98 (1H, m), 7.82 ( 1H, d, 1 = 8.3), 7.76 (1H, d, 1 = 2.0), 7.66 (1H, dd, 1 = 2.0, 8.3), 7.43 (1H dd, 1 = 4.8, 7.4), 7.16 (1H, d, 1 = 8.3), 3.86 (3H, s), 3.83 (3H, s).

Preparation of ^) - 2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylamino-ethyl) methylamino] furan-2-yl} acrylonitrile (compound 48).

According to the procedure used in the production step 1, an amine derivative obtained from Ν, Ν, Ν trimethylethylenediamine (3.06 g) is introduced into 5-bromo-2-furaldehyde (1.75 g) to obtain 5- (4 methylpiperazin-1 -yl) furan-2-carbaldehyde (yield: 1.18 g, 60%). The obtained 5- (4-methylpiperazin-1yl) furan-2-carbaldehyde (1.18 g) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (1.06 g) according to method A (production step 2) to obtain the desired product (yield : 2.06 g, 96%).

Fawn oil. MS (Ε8Ι, t / ζ): 356 (M + H) ⁺ .

Я-NMR (С0С1з) δ: 7.12 (1Н, dd, 1 = 2.2, 8.5), 7.05 (1Н, d, 1 = 2.2), 6.92 (1Н, s) 6.86 (1H, d, 1 = 8.5), 6.83 (1H, d, 1 = 3.7), 5.16 (1H, d, 1 = 3.7), 3.94 ( 3H, s), 3.90 (3H, s), 3.53 (2H, t, 1 = 7.0), 3.07 (3H, s), 2.56 (2H, t, 1 = 3, 7), 2.31 (6H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylaminoethyl) methylamino] furan-2-yl} acrylonitrile hydrochloride (compound 49).

0.1n Hydrochloric acid (12.5 ml) was added to compound 48 (404 mg) to dissolve, and purified water (20 ml) was added to the resulting solution, followed by stirring at room temperature for 20 minutes. The reaction mixture was lyophilized to afford the desired product (yield: 400 mg, 90%).

Tan powder. MS (Ε8Ι, t / ζ): 356 (M-HC1 + H) ⁺ .

Я-NMR (SPS1 ₃ ) δ: 7.11 (1H, dd, 1 = 2.2, 8.5), 7.02 (1H, d, 1 = 2.2), 6.91 (1H, s ), 6.88 (1H, d, 1 = 8.5), 6.70 (1H, d, 1 = 3.7), 5.24 (1H, d, 1 = 3.7), 4.03 (2H, t, 1 = 7.3), 3.94 (3H, s), 3.91 (3H, s), 3.44 (2H, t, 1 = 7.3), 3.11 (3H , s), 2.89 (6H, s).

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] furan-2-yl} acrylonitrile hydrochloride (compound 50).

0.1n Hydrochloric acid (11.8 ml) was added to compound 28 (410 mg) to dissolve, and purified water (20 ml) was added to the solution, followed by stirring at room temperature for 20 minutes. The reaction mixture was lyophilized to afford the desired product (yield: 404 mg, 90%).

Fawn powder. MS (Ε8Ι, t / ζ): 384 (M-HC1 + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.16 (1H, dd, 1 = 2.2, 8.5), 7.05 (1H, d, 1 = 2.2), 6.98 (1H, s ), 6.89 (1H, d, 1 = 8.5), 6.77 (1H, d, 1 = 3.7), 5.41 (1H, d, 1 = 3.7), 4.05 -4.12 (2H, m), 3.94 (3H, s), 3.91 (3H, s), 3.90-3.94 (6H, m), 3.49 (2H, s), 3.18-3.22 (2H, m).

Preparation of Mono (1- {5 - [^) - 2-cyano-2 (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) succinate (compound 51).

Compound 26 (800 mg) was dissolved in pyridine (4 ml), and succinic anhydride (1.13 g) was added to the solution, followed by stirring under reflux for 2 hours. After completion of the reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes The solvent was evaporated to dryness and the residue was extracted with chloroform and purified water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was washed with hexane to obtain the desired product (yield: 954 mg, 93%).

Yellow powder. MS (Ε8Ι, t / ζ): 453 (M-H) ^- .

Я-NMR (DMSO) δ: 1.64-1.66 (2H, m), 1.87-1.89 (2H, m), 2.08-2.13 (2H, m), 2.34 -2.39 (2H, m), 3.21-3.28 (2H, m), 3.59-3.62 (2H, m), 3.77 (3H, s), 3.82 (3H , s), 4.86-4.88 (1H, m), 5.60 (1H, d, 1 = 3.7), 6.96 (1H, d, 1 = 3.4), 7.00 (1H, d, 1 = 8.5), 7.09 (1H, dd, 1 = 2.0, 8.5), 7.16 (1H, d, 1 = 2.0), 7.46 ( 1H, s).

Preparation of Mono (1- {5 - [^) - 2-cyano-2 (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) phosphate (compound 52).

Compound 26 (383 mg) and bis (2,2,2-trichloroethyl) phosphorochloridate (1.64 g) were dissolved in pyridine (4 ml) and the resulting solution was stirred at room temperature for 2 hours. After completion of the reaction, was added to the reaction mixture methanol, followed by stirring for 30 minutes. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 7: 13) to obtain 1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2- yl} piperidin-4-yl-bis (2,2,2-trichloroethyl) phosphate (yield: 663 mg, 88%).

The resulting 1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl-bis (2,2,2-trichloroethyl) phosphate (376 mg) is dissolved in a solvent mixture (5 ml) containing pyridine and acetic acid (4: 1). Zinc powder (353 mg) was added to the solution and everything was stirred at room temperature for 4 hours. Insoluble zinc powder was removed by filtration and GK resin C748 (ΝΉ ₄ ⁺ ) (11 g) was added to the filtrate, followed by stirring at room temperature for

- 17 014555 for 30 minutes. The gummy material was removed by filtration and the solvent was evaporated to dryness. The residue was washed with ethanol to obtain the desired product (yield: 192 mg, 82%).

Fawn powder. MS (EM t / ζ): 433 (M-H) ^- .

Я-NMR (DMSO) δ: 1.68-1.72 (2H, m), 1.93-1.99 (2H, m), 3.24-3.30 (2H, m), 3.60 -3.63 (2H, m), 3.77 (3H, s), 3.82 (3H, s), 4.27-4.30 (1H, m), 5.58 (1H, d, D) = 3.7), 6.96 (1H, d, D = 3.4), 6.99 (1H, d, 1 = 8.5), 7.08 (1H, dd, 1 = 2.0, 8.5), 7.15 (1H, d, 1 = 2.0), 7.44 (1H, s).

Preparation of Mono (1- {5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) phosphate sodium salt (compound 53).

Purified water (10 ml) was added to compound 52 (96 mg) to form a suspension. Resin 1K.C748 (Να) (2 g) was added to the resulting suspension, followed by stirring at room temperature. After the starting materials were dissolved, the gummy substance was removed by filtration and the solvent was evaporated to dryness to obtain the desired product (yield: 93 mg, 96%).

Fawn powder.

MS (E81, t / z): 433 (M-2Ha + H) ⁺ .

Ή-NMR (Ό ₂ Θ) δ: 1.50-1.53 (2H, m), 1.87-1.91 (2H, m), 2.96-2.99 (2H, m), 3 , 53-3.66 (2H, m), 3.64 (3H, s), 3.66 (3H, s), 4.04-4.06 (1H, m), 5.31 (1H, d , 1 = 3.7), 6.64 (1H, d, 1 = 3.9), 6.69-6.72 (2H, m), 6.78-6.81 (1H, m), 6 84 (1H, s).

Preparation of (2) -3- (5-bromofuran-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 54).

5-bromo-2-furaldehyde (350 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (354 mg) according to method A (production step 2) to obtain the desired product (yield: 558 mg, 84%).

Light yellow crystals. MS (APC1, t / ζ): 334 (M + H) ⁺ .

Я-NMR (СОС1з) δ: 7.23 (1Н, d), 7.22 (1Н, d, 1 = 3.7), 7.22 (1Н, dd, 1 = 2.2, 8.5) 7.08 (1H, d, 1 = 2.2), 6.91 (1H, d, 1 = 8.5), 6.51 (1H, d, 1 = 3.7), 3.95 ( 3H, s), 3.93 (3H, s).

Preparation of (E) -3- (3,4-dimethoxyphenyl) -2-thiophen-2-ylacrylonitrile (compound 55).

2- Thiophenacetonitrile (246 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzaldehyde (332 mg) according to method B (production step 2) to obtain the desired product (yield: 262 mg, 48%).

Yellow crystals. MS (APC1, t / ζ): 272 (M + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.64 (1H, d, 1 = 2.0), 7.31-7.36 (2H, m), 7.31 (1H, s), 7.28 ( 1H, dd, 1 = 1.2, 5.1), 7.07 (1H, dd, 1 = 3.7, 5.1), 6.92 (1H, d, 1 = 8.5), 3 97 (3H, s); 3.95 (3H, s).

Preparation of (2) -3- (3,4-dimethoxyphenyl) -2-thiophen-3-ylacrylonitrile (compound 56).

3-thiophenacetonitrile (246 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzaldehyde (332 mg) according to method B (production step 2) to obtain the desired product (yield: 354 mg, 65%).

Light yellow crystals. MS (APC1, t / ζ): 272 (M + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.66 (1Н, d, 1 = 2.0), 7.55 (1Н, dd, 1 = 1.4, 2.9), 7.40 (1Н, dd , 1 = 2.9, 5.1), 7.38 (1H, s), 7.35 (1H, dd, 1 = 1.4, 5.1), 7.33 (1H, dd, 1 = 2.0, 8.0), 6.92 (1H, d, 1 = 8.0), 3.97 (3H, s), 3.95 (3H, s).

Preparation of Mono (1- {5 - [(2) -2-cyano-2 (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) succinate sodium salt (compound 57).

Purified water (10 ml) was added to compound 18 (104 mg) to form a suspension. Resin 1K.C748 (Να) (2 g) was added to the suspension, followed by stirring at room temperature. After the starting materials were dissolved, the gummy substance was removed by filtration and the solvent was evaporated to dryness to obtain the desired product (yield: 102 mg, 94%).

Yellow powder. MS (E81, t / ζ): 469 (Μ-Να) ^- .

Ή-NMR (Ό ₂ Θ) δ: 1.42-1.48 (2H, m), 1.64-1.70 (2H, m), 2.28-2.32 (2H, m), 2 , 39-2.43 (2H, m), 2.72-2.78 (2H, m), 3.05-3.10 (2H, m), 3.52 (3H, s), 3.62 (3H, s), 4.65-4.73 (1H, m), 5.67 (1H, d, 1 = 3.4), 6.45 (1H, d, 1 = 8.1), 6 59-6.61 (2H, m), 6.83 (1H, d, 1 = 3.9), 7.03 (1H, s).

Preparation of Mono (1- {5 - [(2) -2-cyano-2 (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) succinate sodium salt (compound 58).

Purified water (10 ml) was added to compound 51 (101 mg) to form a suspension. Resin 1K.C748 (Να) (2 g) was added to the suspension, followed by stirring at room temperature. After the starting materials were dissolved, the gummy substance was removed by filtration and the solvent was evaporated to dryness to obtain the desired product (yield: 96 mg, 91%).

Yellow powder. MS (EM t / ζ): 453 (Μ-Να) ^- .

Ή-NMR (Ό ₂ Θ) δ: 1.44-1.52 (2H, m), 1.68-1.72 (2H, m), 2.31-2.34 (2H, m), 2 40-2.45 (2H, m), 2.91-2.98 (2H, m), 3.25-3.33 (2H, m), 3.56 (3H, s), 3.59 (3H, s), 4.68-4.76 (1H, m), 5.10-5.12 (1H, m), 6.44-6.49 (2H, m), 6.56-6 57 (3H, m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) methanesulfonate - {5- [4- (2-hydroxyethyl) piperazin-1-yl] thiophen-2-yl} acrylonitrile (compound 59).

Methanesulfonic acid (81.6 μl) and ethanol (10 ml) were added to compound 9 (500 mg), and the mixture was heated to dissolve (external temperature 70 ° C). The solution was again brought to room temperature, followed by stirring overnight. The precipitated crystals are recovered by filtration and the recovered crystals are washed successively with a small amount of ethanol and

- 18 014555 hexane. The crystals were dried thoroughly to obtain the desired product (yield: 530 mg, 85%).

Yellow crystals. MS (Ε8Ι, t / ζ): 400 (M-CH ₃ 8O ₃ H + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 7.98 (1H, s), 7.45 (1H, d, 1 = 4.4), 7.19 (1H, d, 1 = 2.2), 7.11 (1H, dd, 1 = 2.2, 8.5), 7.02 (1H, d, 1 = 8.5), 6.42 (1H, d, 1 = 4.4), 3 , 83 (3H, s), 3.78 (3H, s), 3.75-3.83 (4H, m), 3.57-3.64 (2H, m), 3.253.40 (6H, m ), 2.30 (3H, s).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidine hydrochloride

4-yl-Y- (2-diethylaminoethyl) succinamate (compound 60).

Compound 18 (235 mg) was dissolved in methylene chloride (10 ml) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (105 mg) and Ν-methylmorpholine (66 μl) were added to the solution, followed by stirring for 30 minutes with ice cooling. Then, Ν, Ν-diethylethylenediamine (85 μl) and Ν methylmorpholine (110 μl) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHCl ₃ -MeOH) to obtain the desired product (yield: 287 mg, 95%).

Yellow powder. MS (Ε8Ι, t / ζ): 569 (M-HC1 + H) ⁺ .

Я-NMR ^ C1 ₃ ) δ: 7.60 (1H, m), 7.37 (1H, s), 7.22 (1H, d, 1 = 4.1), 7.13 (1H, dd, 1 = 2.2, 8.3), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 4.1), 6.05 (1H, d,. ) 8.5 Hz), 4.96-5.00 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.50-3.56 (2H, m) , 3.39-3.43 (2H, m), 3.25-3.31 (2H, m), 3.05-3.17 (6H, m), 2.65-2.69 (2H, m), 2.56-2.59 (2H, m), 2.02-2.12 (2H, m), 1.97-2.01 (2H, m), 1.83-1.90 ( 2H, m), 1.39 (6H, t, 1 = 7.3).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidine hydrochloride

4-yl-Y- (3-diethylaminopropyl) succinamate (compound 61).

Compound 18 (235 mg) was dissolved in methylene chloride (10 ml) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (105 mg) and Ν-methylmorpholine (66 μl) were added to the solution, followed by stirring for 30 min with ice cooling. Then ^ N-diethyl-1,3-diaminopropane (94 μl) and Ν-methylmorpholine (110 μl) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHC13 -MeOH) to obtain the desired product (yield: 279 mg, 90%).

Yellow powder. MS (Ε8Ι, t / ζ): 583 (M-HC1 + H) ⁺ .

Я-NMR ^ C1 ₃ ) δ: 7.60 (1H, m), 7.37 (1H, s), 7.22 (1H, d, 1 = 4.1), 7.13 (1H, dd, 1 = 2.2, 8.3), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 4.1), 6.05 (1H, d, 1 = 8.5), 4.96-5.00 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.50-3.56 (2H, m), 3.39-3.43 (2H, m), 3.25-3.31 (2H, m), 3.05-3.17 (6H, m), 2.65-2.69 (2H, m) ), 2.56-2.59 (2H, m), 2.02-2.12 (2H, m), 1.97-2.01 (2H, m), 1.83-1.90 (2H , m) 1.39 (6H, t, 1 = 7.3).

(1) Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldimethylaminoacetate.

Compound 6 (3.70 g) was dissolved in pyridine (100 ml) and Ν, Ν-dimethylglycine (5.15 g) was added to the solution, followed by stirring at room temperature for 1 h. Next, p-toluenesulfonyl chloride ( 9.43 g), followed by stirring at reflux for 12 hours. After completion of the reaction, the solvent was evaporated to dryness. Chloroform (800 ml) was added to the residue, and the mixture was washed three times with water. The pH of the aqueous layer is checked by litmus test and adjusted to 4-5 using 1N. aqueous hydrochloric acid.

The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCl ₃ -hexane) to obtain the desired product (yield: 3.48 g, 76%).

Yellow powder.

MS (Ε8Ι, t / ζ): 456 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.36 (1Н, d), 7.22 (1Н, d, 1 = 4.1), 7.13 (1Н, dd, 1 = 2.2, 8.3 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.05 (1H, d, 1 = 4.1), 5.03 -5.09 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.54-3.60 (2H, m), 3.24-3.30 (2H , m), 3.19 (2H, s), 2.37 (6H, s), 2.02-2.07 (2H, m), 1.83-1.91 (2H, m).

(2) Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldimethylaminoacetate p-toluenesulfonate (compound 62).

Compound 6 (370 mg) was dissolved in toluene (80 ml), and Ν, Ν dimethylglycine hydrochloride (140 mg) and toluenesulfonic acid monohydrate (380 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHC13-MeOH) to obtain the desired product (yield: 38 mg, 7.7%).

Yellow powder. MS (Ε8Ι, t / ζ): 456 (M + H) ⁺ .

Я-NMR (DMSO) δ: 7.94 (1H, s), 7.49 (4H, d, 1 = 7.8), 7.43 (1H, d, 1 = 4.1), 7.17 (1H, d, 1 = 2.2), 7.12 (4H, d, 1 = 7.8), 7.09 (1H, dd, 1 = 2.2, 8.5), 7.00 ( 1H, d, 1 = 8.5), 6.32 (1H, d, 1 = 4.1), 5.09-5.12 (1H, m), 4.26 (2H, s), 3, 83 (3H, s), 3.78 (3H, s), 3.51-3.55 (2H, m), 3.31-3.37 (2H, m), 2.89 (6H, s) 2.29 (6H, s), 2.02-2.06 (2H, m), 1.781.82 (2H, m).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yl [1,4 '] bipiperidinyl-1'-carboxylate hydrochloride ( compound 63).

- 19 014555

Compound 6 (2.00 g) was dissolved in pyridine (50 ml), and 1-chlorocarbonyl-4 piperidinopiperidine (2.50 g) was added to the solution, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction mixture methanol is added, followed by stirring for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform and purified water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate to give the desired product (yield: 974 mg, 30%)

Yellow powder. MS (Ε8Ι, t / ζ): 565 (M-HC1 + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.37 (1Н, d), 7.22 (1Н, d, 1 = 4.4), 7.13 (1Н, dd, 1 = 2.0, 8.3 ), 7.04 (1H, d, 1 = 2.0), 6.87 (1H, d, 1 = 8.3), 6.05 (1H, d, 1 = 4.4), 4.90 -4.94 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.48-3.54 (2H, m), 3.25-3.34 (2H , m), 2.74 (2H, m), 2.42-2.53 (7H, m), 2.01-2.06 (2H, m), 1.83-1.85 (4H, m ), 1.60-1.61 (4H, m), 1.45 (4H, m).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yl-4- [1,4 '] bipiperidinyl-1'- hydrochloride il-4-oxobutylate (compound 64).

Compound 18 (1.00 g) was dissolved in methylene chloride (20 ml) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (448 mg) and Ν-methylmorpholine (258 μl) were added to the solution, followed by stirring for 30 min under ice cooling. Then, 4-piperidinopiperidine (429 mg) and Ν methylmorpholine (430 μl) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness and the precipitate was recrystallized from ethyl acetate to obtain the desired product (yield: 1.37 g, 98%).

Yellow powder. MS (Ε8Ι, t / ζ): 621 (M-HC1 + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 7.38 (1Н, d), 7.22 (1Н, d, 1 = 4.4), 7.13 (1Н, dd, 1 = 2.4, 8.3 ), 7.04 (1H, d, 1 = 2.4), 6.87 (1H, d, 1 = 8.3), 6.05 (1H, d, 1 = 4.4), 5.00 -5.04 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.50-3.56 (2H, m), 3.26-3.32 (2H , m), 3.00-3.06 (2H, m), 2.50-2.72 (11H, m), 1.95-2.04 (2H, m), 1.87-1.90 (4H, m), 1.65-1.70 (4H, m), 1.421.55 (4H, m).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3-quinolin-4-ylacrylonitrile (compound 65).

4-Quinolinecarboxaldehyde (500 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (564 mg) according to method A (production step 2) to obtain the desired product (yield: 522 mg, 52%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 317 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 9.04 (1Н, d, 1 = 4.5), 8.20 (1Н, d, 1 = 8.5), 8.07 (1Н, s), 7, 99 (1H, d, 1 = 8.5), 7.87 (1H, d, 1 = 4.5), 7.77-7.81 (1H, m), 7.61-7.65 (1H , m), 7.39 (1H, dd, 1 = 8.5, 2.3), 7.25 (1H, d, 1 = 2.3), 6.98 (1H, d, 1 = 8, 5), 4.00 (3H, s), 3.97 (3H, s).

Preparation of (2) -3-benzo [b] thiophen-3-yl-2- (3,4-dimethoxyphenyl) acrylonitrile (compound 66).

Benzo [b] thiophene-3-carboxaldehyde (200 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (218 mg) according to method A (production step 2) to obtain the desired product (yield: 365 mg, 92%).

Light yellow crystals. MS (ARO, t / ζ): 322 (M + H) ⁺ .

Ή-NMR (SBS _{1 3} ) δ: 8.56 (1Н, s), 7.93 (1Н, d, 1 = 7.3), 7.89 (1Н, d, 1 = 7.3), 7, 72 (1H, s), 7.43-7.51 (2H, m), 7.32 (1H, dd, 1 = 2.3, 8.5), 7.20 (1H, d, 1 = 2 3), 6.96 (1H, d, 1 = 8.5), 3.99 (3H, s), 3.95 (3H, s).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (1-methyl-1H-benzimidazol-2-yl) acrylonitrile (compound 67).

1-Methyl-2-formylbenzimidazole (200 mg) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (221 mg) according to method A (production step 2) to obtain the desired product (yield: 369 mg, 93%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 320 (M + H) ⁺ .

Я-NMR (SBS _{1 3} ) δ: 7.88-7.92 (1H, m), 7.37 (1H, s), 7.32-7.39 (4H, m), 7.24 (1H, d, 1 = 2.3), 6.94 (1H, d, 1 = 8.5), 3.98 (3H, s), 3.95 (3H, s), 3.89 (3H, s) .

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- (1-methyl-1H-indol-3yl) acrylonitrile (compound 68).

1- Methylindole-3-carboxaldehyde (200 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (223 mg) according to method A (production step 2) to obtain the desired product (yield: 292 mg, 73%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 319 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.29 (1Н, s), 7.78 (1Н, d, 1 = 8.0), 7.74 (1Н, s), 7.31-7.36 ( 1H, m), 7.37-7.42 (1H, m), 7.22-7.28 (3H, m), 7.16 (1H, d, 1 = 2.3), 6.93 ( 1H, d, 1 = 8.5), 3.98 (3H, s), 3.93 (3H, s), 3.91 (3H, s).

Preparation of (2) -3-benzofuran-2-yl-2- (3,4-dimethoxyphenyl) acrylonitrile (compound 69).

2- Benzofurancarboxaldehyde (166 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (201 mg) according to method A (production step 2) to obtain the desired product (yield: 265 mg, 77%).

Yellow crystals. MS (ARO, t / ζ): 306 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 7.65 (1H, br.s.d, 1 = 7.8), 7.55 (1H, br.s.d, 1 = 8.3), 7.48 (1H, br. .s), 7.36-7.42 (2H, m), 7.31 (1H, dd, 1 = 2.4, 8.5), 7.29 (1H, br.s.d, 1 = 7, 8), 7.17 (1H, d, 1 = 2.4), 6.94 (1H, d, 1 = 8.5), 3.98 (3H, s), 3.94 (3H,

- 20 014555

from).

Preparation of SH) -2- (2-chloroquinolin-3-yl) -2- (3,4-dimethoxyphenyl) -3-quinolin-4-ylacrylonitrile (compound 70).

2-Chloro-3-quinolinecarboxaldehyde (200 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (185) according to method A (production step 2) to obtain the desired product (yield: 311 mg, 85%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 351 (M + H) ⁺ .

Я-NMR (CBC1 ₃ ) δ: 8.87 (1H, s), 8.05 (1H, brd, 1 = 8.0), 7.96 (1H, brd, 1 = 8.0 ), 7.83 (1H, s), 7.84-7.89 (1H, m), 7.61-7.66 (1H, m), 7.37 (1H, d, 1 = 2.2 8.5), 7.22 (1H, d, 1 = 2.2), 6.98 (1H, d, 1 = 8.5), 3.99 (3H, s), 3.96 (3H , from).

Preparation of (E) -2-benzotriazol-1-yl-3- (3,4-dimethoxyphenyl) acrylonitrile (compound 71).

3.4- Dimethoxybenzaldehyde (210 mg) is subjected to a condensation reaction with 1H-benzotriazole-1-acetonitrile (200 mg) according to method B (production step 2) to obtain the desired product (yield: 133 mg, 34%).

White crystals (colorless). MS (Ε8Ι, t / ζ): 307 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 8.15 (1Н, br.s.d, 1 = 8.5), 7.90 (1Н, br.s.d, 1 = 8.5), 7.83 (1Н, s ), 7.69 (1H, d, 1 = 2.2), 7.62-7.66 (1H, m), 7.47-7.51 (1H, m), 7.44 (1H, dd , 1 = 2.2, 8.5), 6.99 (1H, d, 1 = 8.5), 4.00 (3H, s), 3.99 (3H, s).

Preparation of SH) -2-benzofuran-3-yl-3- (3,4-dimethoxyphenyl) acrylonitrile (compound 72).

3.4-dimethoxybenzaldehyde (106 mg) is subjected to a condensation reaction with benzotriazole-3acetonitrile (100 mg) according to method B (production step 2) to obtain the desired product (yield: 110 mg, 57%).

White needle crystals (colorless). MS (ARCE t / ζ): 306 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 7.97 (1Н, s), 7.90-7.94 (1Н, m), 7.69 (1Н, d, 1 = 2.0), 7.57 ( 1H, s), 7.56-7.58 (1H, m), 7.35-7.43 (3H, m), 6.95 (1H, d, 1 = 8.5), 3.99 ( 3H, s), 3.96 (3H, s).

Preparation of SH) -3- (2-chloro-6-methoxyquinolin-3-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 73).

2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (500 mg) was condensed with 3,4dimethoxybenzyl cyanide (400 mg) according to method A (production step 2) to obtain the desired product (yield: 784 mg, 91%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 381 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.78 (1Н, s), 7.93 (1Н, d, 1 = 9.3), 7.82 (1Н, s), 7.44 (1Н, dd, 1 = 2.9, 9.3), 7.36 (1H, dd, 1 = 2.2, 8.5), 7.22 (1H, d, 1 = 2.2), 7.19 (1H d, 1 = 2.9), 6.97 (1H, d, 1 = 8.5), 4.00 (3H, s), 3.97 (3H, s), 3.96 (3H, s )

Preparation of (E) -2-benzothiazol-2-yl-3- (3,4-dimethoxyphenyl) acrylonitrile (compound 74).

3.4- Dimethoxybenzaldehyde (191 mg) is subjected to a condensation reaction with 2-benzothiazoleacetonitrile (200 mg) according to method B (production step 2) to obtain the desired product (yield: 330 mg, 89%).

Yellow powder. MS (Ε8Ι, t / ζ): 323 (M + H) ⁺ .

Ή-NMR (ΟΌΟ1 ₃ ) δ: 8.18 (1Н, s), 8.05-8.08 (1Н, m), 7.89-7.92 (1Н, m), 7.83 (1Н, d, 1 = 2.2), 7.50-7.55 (2H, m), 7.40-7.44 (1H, m), 6.97 (1H, d, 1 = 8.5), 3.99 (3H, s); 3.98 (3H, s).

Preparation of SH) -3- (2,3-dihydrobenzofuran-5-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 75).

2,3-Dihydrobenzofuran-5-carboxaldehyde (150 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (180 mg) according to method A (production step 2) to obtain the desired product (yield: 154 mg, 50%).

Yellow powder. MS (AWP t / ζ): 308 (M + H) ⁺ .

Ή-NMR (ΟΌΟ1 ₃ ) δ: 7.93 (1Н, br.s), 7.55 (1Н, d, 1 = 1.6, 8.4), 7.34 (1Н, s), 7, 22 (1H, dd, 1 = 2.2, 8.4), 7.12 (1H, d, 1 = 2.2), 6.91 (1H, d, 1 = 8.5), 6.85 (1H, d, 1 = 8.5), 4.66 (2H, t, 1 = 8.7), 3.96 (3H, s), 3.92 (3H, s), 3.29 (2H , t, 1 = 8.7).

Preparation of SH) -2- (3,4-dimethoxyphenyl) -3- [5- (4-fluorophenyl) isoxazol-3-yl] acrylonitrile (compound 76).

5- (4-Fluorophenyl) isoxazole-3-carboxaldehyde (200 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (185 mg) according to method A (production step 2) to obtain the desired product (yield: 150 mg, 41%).

Yellow powder. MS (Ε8Ι, t / ζ): 351 (M + H) ⁺ .

Ή-NMR (ΟΌΟ1 ₃ ) δ: 3.95 (3H, s), 3.98 (3H, s), 6.95 (1H, d, 1 = 8.5), 7.18-7.24 ( 3H, m), 7.35 (1H, dd, 1 = 2.3, 8.5), 7.44 (1H, s), 7.59 (1H, s), 7.87 (2H, dd, 1 = 2.5, 9.5).

Preparation of SH) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methoxyphenyl) isoxazol-3-yl] acrylonitrile (compound 77).

5- (4-Methoxyphenyl) isoxazole-3-carboxaldehyde (200 mg) is subjected to a condensation reaction with 3,4dimethoxybenzyl cyanide (174 mg) according to method A (production step 2) to obtain the desired product (yield: 127 mg, 36%).

Yellow powder. MS (Ε8Ι, t / ζ): 363 (M + H) ⁺ .

- 21 014555

Я-NMR (С0С1 ₃ ) δ: 7.81 (1Н, d, 1 = 9.4), 7.59 (1Н, s), 7.37 (1Н, s), 7.35 (1Н, dd, 1 = 2.2, 8.5), 7.19 (1H, d, 1 = 2.2), 7.01 (2H, d, 1 = 9.4), 6.95 (1H, d, 1 = 8.5), 3.97 (3H, s), 3.95 (3H, s), 3.89 (3H, s).

Preparation of ^) - 2- (3,4-dimethoxyphenyl) -3-quinolin-2-ylacrylonitrile (compound 78).

2-Quinolinecarboxaldehyde (200 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (225 mg) according to method A (production step 2) to obtain the desired product (yield: 252 mg, 63%).

Yellow powder. MS (E§1, t / ζ): 316 (M + H) ⁺ .

Я-NMR (CBC1 ₃ ) δ: 8.27 (1H, d, 1 = 8.5), 8.18 (1H, d, 1 = 8.5), 8.15 (1H, d, 1 = 8 5), 7.86 (1H, br.s.d, 1 = 8.5), 7.76 (1H, s), 7.74-7.80 (1H, m), 7.58-7.62 (1H, m), 7.43 (1H, dd, 1 = 2.2, 8.3), 7.29 (1H, d, 1 = 2.2), 6.96 (1H, d, 1 = 8.3), 3.99 (3H, s), 3.96 (3H, s).

Obtaining ^) - 2- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-2-yl-acrylonitrile (compound 79).

2-Chloro-6-methoxyquinoline carboxaldehyde (222 mg) was condensed with 2 pyridine acetonitrile (118 mg) according to method B (production step 3) to obtain the desired product (yield: 311 mg, 97%).

Light yellow crystals. MS (E1, t / z): 322 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 8.883 (1Н, s), 8.875 (1Н, s), 8.71-8.74 (1Н, m), 7.94 (1Н, d, 1 = 9.1) 7.83-7.87 (2H, m), 7.46 (1H, d, 1 = 2.8, 9.1), 7.35-7.39 (1H, m), 7.21 ( 1H, d, 1 = 2.8), 3.97 (3H, s).

Preparation ^) - 3- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-3-ylacrylonitrile (compound 80).

2-Chloro-6-methoxyquinoline carboxaldehyde (222 mg) is subjected to a condensation reaction with 3pyridine acetonitrile (118 mg) according to method B (production step 3) to obtain the desired product (yield: 251 mg, 78%).

White crystals. MS (E1, t / z): 322 (M + H) ⁺ .

Я-NMR (SPS1 ₃ ) δ: 9.03 (1H, d, 1 = 2.4), 8.84 (1H, s), 8.72 (1H, dd, 1 = 1.5, 4.9 ), 8.03-8.07 (1H, m), 8.02 (1H, s), 7.95 (1H, d, 1 = 9.0), 7.44-7.50 (2H, m ), 7.21 (1H, d, 1 = 2.7), 3.97 (3H, s).

Preparation of (E) -3- (2-chloro-6-methoxyquinolin-3-yl) -2-thiophen-2-ylacrylonitrile (compound 81).

2-Chloro-6-methoxyquinoline carboxaldehyde (222 mg) was subjected to a condensation reaction with 2 thiophenacetonitrile (123 mg) according to method B (production step 3) to obtain the desired product (yield: 301 mg, 92%).

Light yellow crystals. MS (E1, t / z): 327 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.77 (1Н, s), 7.92 (1Н, d, 1 = 9.3), 7.79 (1Н, s), 7.50 (1Н, dd, 1 = 1.2, 3.7), 7.44 (1H, dd, 1 = 2.7, 9.3), 7.42 (1H, dd, 1 = 1.5, 6.6), 7 18 (1H, d, 1 = 2.7), 7.14 (1H, dd, 1 = 3.7, 5.1), 3.96 (3H, s).

Preparation of ^) - 2- (2-chloro-6-methoxyquinolin-3-yl) -2-thiophen-3-ylacrylonitrile (compound 82).

2-Chloro-6-methoxyquinolinecarboxaldehyde (222 mg) was condensed with 3-thiophenacetonitrile (123 mg) according to method B (production step 3) to obtain the desired product (yield: 273 mg, 83%).

Light yellow crystals. MS (E1, t / z): 327 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.78 (1Н, s), 7.92 (1Н, d, 1 = 9.1), 7.85 (1Н, s), 7.72-7.75 ( 1H, m), 7.46-7.48 (2H, m), 7.44 (1H, dd, 1 = 2.8, 9.1), 7.18 (1H, d, 1 = 2.8 ), 3.96 (3H, s).

Preparation of (E) -2-benzotriazol-1-yl-3- (2-chloro-6-methoxyquinolin-3-yl) acrylonitrile (compound

83).

2-Chloro-6-methoxyquinoline carboxaldehyde (111 mg) is subjected to a condensation reaction with 1Nbenzotriazole-1-acetonitrile (79 mg) according to method B (production step 3) to obtain the desired product (yield: 129 mg, 71%).

White powder. MS (E1, t / z): 362 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.85 (1Н, s), 8.21 (1Н, d, 1 = 8.3), 8.36 (1Н, s), 8.00 (1Н, t, 1 = 9.3), 7.98 (1H, t, 1 = 9.3), 7.69-7.73 (1H, m), 7.53-7.57 (1H, m), 7, 51 (1H, dd, 1 = 2.8, 9.3), 7.24 (1H, d, 1 = 2.8), 3.99 (3H, s).

Preparation of (E) -2-benzotriazol-2-yl-3- (2-chloro-6-methoxyquinolin-3-yl) acrylonitrile (compound

84).

2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (111 mg) is subjected to a condensation reaction with 2 benzothiazole acetonitrile (87 mg) according to method B (production step 3) to obtain the desired product (yield: 148 mg, 78%).

Yellow crystals. MS (E§1, t / z): 378 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 8.99 (1Н, s), 8.65 (1Н, s), 8.17 (1Н, d, 1 = 8.1), 7.90-7.95 ( 2H, m), 7.55-7.61 (1H, m), 7.46-7.52 (2H, m), 7.22 (1H, d, 1 = 2.7), 3.98 ( 3H, s).

Obtaining ^) - 2-pyridin-2-yl-3-quinolin-4-ylacrylonitrile (compound 85).

4-Quinolinecarboxaldehyde (157 mg) is subjected to a condensation reaction with 2-pyridineacetonitrile (118 mg) according to method B (production step 3) to obtain the desired product (yield: 138 mg, 54%).

Light pink crystals. MS (E§1, t / ζ): 258 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 9.22 (1H, s), 9.06 (1H, d, 1 = 4.4), 8.72-8.74 (1H, m), 8.21 ( 1H, D, 1 = 8.3), 8.10 (1H, d, 1 = 8.3), 7.96 (1H, d, 1 = 4.4), 7.80-7.83 (2H , m), 7.75-7.82 (1H, m), 7.62-7.67 (1H, m), 7.38-7.41 (1H, m).

Obtaining ^) - 2-pyridin-3-yl-3-quinolin-4-ylacrylonitrile (compound 86).

- 22 014555

4-Quinolinecarboxaldehyde (157 mg) is subjected to a condensation reaction with 3-pyridineacetonitrile (118 mg) according to method B (production step 3) to obtain the desired product (yield: 76 mg, 29%).

White powder. MS (Ε8Ι, t / ζ): 258 (M + H) ⁺ .

Я-NMR (CBC1 ₃ ) δ: 9.08 (1H, d, 1 = 4.6), 9.07 (1H, d, 1 = 2.4), 8.74 (1H, d, 1 = 1 6, 4.8), 8.27 (1H, s), 8.23 (1H, d, 1 = 7.8), 8.09 (1H, ddd, 1 = 1.7, 2.4, 8.1), 7.98 (1H, d, 1 = 8.5), 7.91 (1H, d, 1 = 4.8), 7.80-7.84 (1H, m), 7.647, 68 (1H, m), 7.49 (1H, dd, 1 = 4.8, 8.1).

Preparation of (E) -3-quinolin-4-yl-2-thiophen-2-ylacrylonitrile (compound 87).

4-Quinolinecarboxaldehyde (157 mg) is subjected to a condensation reaction with 2-thiophenacetonitrile (123 mg) according to method B (production step 3) to obtain the desired product (yield: 175 mg, 67%).

Light yellow crystals. MS (Ε8Ι, t / ζ): 263 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 9.03 (1H, d, 1 = 4.4), 8.20 (1H, d, 1 = 8.5), 8.03 (1H, s), 7, 99 (1H, d, 1 = 8.5), 7.89 (1H, dd, 1 = 0.9, 4.4), 7.78-7.82 (1H, m), 7.63-7 67 (1H, d), 7.53 (1H, dd, 1 = 1.2, 3.7), 7.45 (1H, dd, 1 = 1.2, 5.1), 7.16 ( 1H, dd, 1 = 3.7, 5.1).

Obtaining ^) - 3-quinolin-4-yl-2-thiophen-3-ylacrylonitrile (compound 88).

4-Quinolinecarboxaldehyde (157 mg) is subjected to a condensation reaction with 3-thiophenacetonitrile (123 mg) according to method B (production step 3) to obtain the desired product (yield: 81 mg, 31%).

Yellow powder. MS (Ε8Ι, t / ζ): 263 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 9.03 (1Н, d, 1 = 4.4), 8.20 (1Н, d, 1 = 8.4), 8.09 (1Н, s), 7, 98 (1H, d, 1 = 8.4), 7.87 (1H, d, 1 = 4.4), 7.76-7.82 (2H, m), 7.61-7.65 (1H , m) 7.50 (1H, s), 7.49 (1H, s).

Preparation of (E) -3-benzo [b] thiophen-3-yl-2-thiophen-2-ylacrylonitrile (compound 89).

Benzo [b] thiophene-3-carboxaldehyde (81 mg) was subjected to a condensation reaction with 2-thiophenacetonitrile (62 mg) according to method B (production step 3) to obtain the desired product (yield: 40 mg, 30%).

Yellow powder. MS (Ε8Ι, t / ζ): 268 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 8.55 (1Н, s), 7.91-7.93 (1Н, m), 7.89 (1Н, dd, 1 = 1.2, 7.3), 7.67 (1H, dd), 7.49 (1H, dd, 1 = 1.2, 7.9), 7.46 (1H, dd, 1 = 1.2, 7.9), 7.42 (1H, dd, 1 = 1.2, 3.7), 7.34 (1H, dd, 1 = 1.2, 5.1), 7.11 (1H, dd, 1 = 3.7, 5 ,one).

Preparation of (E) -3-benzo [b] thiophen-3-yl-2-benzothiazol-2-ylacrylonitrile (compound 90).

Benzo [b] thiophene-3-carboxaldehyde (81 mg) was subjected to a condensation reaction with 2-benzothiazoleacetonitrile (87 mg) according to method B (production step 3) to obtain the desired product (yield: 111 mg, 69%).

Yellow powder. MS (Ε8Ι, t / ζ): 319 (M + H) ⁺ .

Ή-NMR (SBS1 ₃ ) δ: 8.89 (1H, s), 8.60 (1H, s), 8.11 (1H, br.s.d, 1 = 8.2), 8.06 (1H, br.s.d, 1 = 7.8), 7.91-7.96 (2H, m), 7.53-7.58 (2H, m), 7.43-7.52 (2H, m).

Obtaining ^) - 3-benzofuran-2-yl-1-benzofuran-3-ylacrylonitrile (compound 91).

2-Benzofurancarboxaldehyde (73 mg) is subjected to a condensation reaction with benzofuran-3acetonitrile (79 mg) according to method B (production step 3) to obtain the desired product (yield: 110 mg, 77%).

Yellow powder. MS (Ε8Ι, t / ζ): 319 (M + H) ⁺ .

Ή-NMR (СОС1 ₃ ) δ: 8.06 (1Н, s), 7.92-7.96 (1Н, m), 7.66 (1Н, br.s.d, 1 = 7.8), 7, 58 (1H, s), 7.56-7.60 (2H, m), 7.47 (1H, s), 7.38-7.45 (3H, m), 7.28-7.32 ( 1H, m).

Preparation of (E) -2-benzothiazol-2-yl-3- (1-methyl-1H-indol-3-yl) acrylonitrile (compound 92).

1- Methylindole-3-carboxaldehyde (79 mg) is subjected to a condensation reaction with 2 benzothiazoleacetonitrile (87 mg) according to method B (production step 3) to obtain the desired product (yield: 157 mg, 99%).

Yellow powder. MS (Ε8Ι, t / ζ): 316 (M + H) ⁺ .

Я-NMR (SBS1 ₃ ) δ: 8.56 (1H, s), 8.50 (1H, s), 8.03-8.07 (1H, m), 7.90-7.94 (1H, m), 7.86-7.90 (1H, m), 7.48-7.53 (1H, m), 7.33-7.45 (4H, m), 3.95 (3H, s) .

Preparation ^) - 3- (10-chloranthracen-9-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile (compound 93).

10-Chloro-9-anthraldehyde (500 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (368 mg) according to method A (production step 2) to obtain the desired product (yield: 466 mg, 56%).

Yellow powder. MS (AWP t / ζ): 400 (M + H) ⁺ .

Я-NMR (СОС1 ₃ ) δ: 8.61 (2Н, d, 1 = 8.5), 8.27 (1Н, s), 8.09 (2Н, d, 1 = 8.5), 7, 62-7.68 (2H, m), 7.55-7.61 (2H, m), 7.48 (1H, dd, 1 = 2.2, 8.5), 7.35 (1H, d) , 1 = 2.2), 7.02 (1H, d, 1 = 8.5), 4.01 (3H, s), 3.99 (3H, s).

Obtaining ^) - 2- (3,4-dimethoxyphenyl) -3-naphthalen-2-ylacrylonitrile (compound 94).

2- Naphthaldehyde (500 mg) is subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (567 mg) according to method A (production step 2) to obtain the desired product (yield: 872 mg, 86%).

Yellow powder. MS (AWP, t / ζ): 316 (M + H) ⁺ .

Ή-NMR (SBS1 ₃ ) δ: 8.27 (1H, s), 8.07 (1H, dd, 1 = 1.7, 8.8), 7.84-7.93 (3H, m), 7.59 (1H, s), 7.51-7.58 (2H, m), 7.32 (1H, dd, 1 = 2.2, 8.5), 7.20 (1H, d, 1 = 2.2), 6.94 (1H, d, 1 = 8.5), 3.99 (3H, s), 3.94 (3H, s).

Obtaining ^) - 3- (3,4-dimethoxyphenyl) -3-phenanthren-9-ylacrylonitrile (compound 95).

Phenanthrene-9-aldehyde (250 mg) is condensed with 3,4-dimethoxybenzyl cyanide

23 014555 (214 mg) according to method A (production step 2) to obtain the desired product (yield: 278 mg, 63%).

Yellow powder. MS (ΆΡ8Ι, t / ζ): 366 (M + H) ⁺ .

^! H-NMR (SPS1 ₃ ) δ: 8.77 (1H, d, 1 = 7.8), 8.70 (1H, d, 1 = 7.8), 8.26 (1H, s), 8, 15 (1H, d, 1 = 1.2), 7.99-8.02 (2H, m), 7.70-7.76 (2H, m), 7.63-7.68 (2H, m ), 7.40 (1H, dd, 1 = 2.4, 8.3), 7.28 (1H, d, 1 = 2.4), 6.99 (1H, d, 1 = 8.3) 4.00 (3H, s); 3.97 (3H, s).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldiethylaminoacetate p-toluenesulfonate (compound 96).

Compound 6 (480 mg) was dissolved in toluene (100 ml) and Ν, Ν'-diethylglycine sodium salt (296 mg) and p-toluenesulfonic acid monohydrate (490 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHC13-MeOH) to obtain the desired product (yield: 237 mg, 37.7%).

Yellow powder. MS (Ε8Ι, t / ζ): 484 (M + H) ⁺ .

^! H-NMR (DMSO) δ: 7.94 (1H, s), 7.49 (4H, d, 1 = 7.8), 7.43 (1H, d, 1 = 4.1), 7.17 (1H, d, 1 = 2.2), 7.12 (4H, d, 1 = 7.8), 7.09 (1H, dd, 1 = 2.2, 8.5), 7.00 ( 1H, d, 1 = 8.5), 6.32 (1H, d, 1 = 4.1), 5.09-5.12 (1H, m), 4.26 (2H, s), 3, 83 (3H, s), 3.78 (3H, s), 3.51-3.55 (2H, m), 3.31-3.37 (2H, m), 3.22 (4H, q, 1 = 7.1), 2.29 (6H, s), 2.02-2.06 (2H, m), 1.78-1.82 (2H, m), 1.21 (6H, t, 1 = 7.1).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldiethylcarbamate (compound 97).

Compound 6 (150 mg) was dissolved in pyridine (1 ml), and diethylcarbamoyl chloride (55 mg) was added to the solution, followed by stirring under reflux for 2 hours. After completion of the reaction, methanol was added to the reaction mixture and then stirred for further 30 min. The solvent was evaporated to dryness and the residue was extracted with chloroform and purified water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate to give the desired product (yield: 40.6 mg, 21.3%).

Yellow powder. MS (Ε8Ι, t / ζ): 470 (M + H) ⁺ .

^! H-NMR (COC1 ₃ ) δ: 7.37 (1H, d), 7.23 (1H, d, 1 = 4.4), 7.13 (1H, dd, 1 = 2.2, 8.5 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.05 (1H, d, 1 = 4.4), 4.93 -4.97 (1H, m), 3.74 (3H, s), 3.90 (3H, s), 3.48-3.54 (2H, m), 3.30-3.36 (6H , m), 2.01-2.08 (2H, m), 1.83-1.91 (2H, m), 1.14 (6H, t, 1 = 7.1).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yl-Y- (2-diethylaminoethyl) -Y-methyl succinamate hydrochloride (compound 98).

Compound 18 (500 mg) was dissolved in methylene chloride (10 ml) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (224 mg) and Ν-methylmorpholine (129 μl) were added to the solution, followed by stirring under cooling ice for 30 minutes Then, HH-diethyl-I-methylethylenediamine (166 μl) and Ν-methylmorpholine (215 μl) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHCl ₃ - MeOH) to obtain the desired product (yield: 503 mg, 76%).

Yellow powder. MS (Ε8Ι, t / ζ): 583 (M + H) ⁺ .

^! H-NMR (SPS1 ₃ ) δ: 7.60 (1H, m), 7.37 (1H, s), 7.22 (1H, d, 1 = 4.1), 7.13 (1H, dd, 1 = 2.2, 8.3), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 4.1), 6.05 (1H, d, 1 = 8.5 Hz), 4.96-5.00 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.50-3.56 (2H, m) , 3.39-3.43 (2H, m), 3.25-3.31 (2H, m), 3.05-3.17 (6H, m), 3.13 (3H, s), 2 65-2.69 (2H, m), 2.56-2.59 (2H, m), 2.02-2.12 (2H, m), 1.97-2.01 (2H, m) 1.83-1.90 (2H, m); 1.39 (6H, t, 1 = 7.3).

Preparation of 1- [5 - [(2) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yl-Y- (4-diethylaminophenyl) succinamate hydrochloride (compound 99).

Compound 18 (500 mg) was dissolved in methylene chloride (10 ml) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (224 mg) and Ν-methylmorpholine (129 μl) were added to the solution, followed by stirring under cooling ice for 30 minutes Then ^ N-diethyl-1,4-phenylenediamine (209 μl) and Ν-methylmorpholine (215 μl) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography (CHC1 ₃ -MeOH) to obtain the desired product (yield: 322 mg, 40%).

Yellow powder. MS (Ε8Ι, t / ζ): 617 (M + H) ⁺ .

^! H-NMR (SPS1 ₃ ) δ: 7.91 (1H, s), 7.40 (1H, d, 1 = 4.4), 7.30 (2H, d, 1 = 8.5), 7, 17 (1H, d, 1 = 2.2), 7.09 (1H, dd, 1 = 2.2, 8.3), 7.00 (1H, d, 1 = 8.8), 6.57 (2H, d, 1 = 8.8), 6.27 (1H, d, 1 = 4.1), 4.91-4.95 (1H, m), 3.83 (3H, s), 3 78 (3H, s), 3.44-3.49 (2H, m), 3.25-3.30 (6H, m), 2.57-2.60 (4H, m), 1.91 -1.97 (2H, m), 1.71-1.74 (2H, m), 1.03 (6H, t, 1 = 6.8).

Preparation of (2) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1yl] thiophen-2-yl} acrylonitrile acid sulfate (compound 100).

0.1 mol / L sulfuric acid (6.36 ml) and purified water (18.65 ml) were added to compound 9 (500 mg) and the mixture was heated to dissolve (outside temperature: 90 ° C). The solution was again brought to room temperature and allowed to stand overnight. Precipitated crystals are collected by filtration and the recovered crystals are washed successively with a small amount of purified

- 24 014555 water and hexane. The crystals were dried thoroughly to obtain the desired product (yield: 560 mg, about 100%).

Yellowish-orange crystals. MS (E§1, t / ζ): 400 (M-0.5H ₂ §O ₄ + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 7.95 (1H, s), 7.43 (1H, d, 1 = 4.4), 7.18 (1H, d, 1 = 2.2), 7.10 (1H, dd, 1 = 2.2, 8.5), 7.01 (1H, d, 1 = 8.5), 6.35 (1H, d, 1 = 4.4), 3 , 83 (3H, s), 3.78 (3H, s), 3.62-3.68 (2H, m), 3.38-3.50 (4H, m), 2.853.05 (6H, m )

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] thiophen2-yl} acrylonitrile sulfate (compound 101).

To compound 9 (500 ml) was added 0.1 mol / L sulfuric acid (12.70 mg) and purified water (12.30 ml) and the mixture was heated to dissolve (outside temperature: 90 ° C). The solution was again brought to room temperature and allowed to stand overnight. Precipitated crystals are collected by filtration and the recovered crystals are washed successively with a small amount of purified water and hexane. The crystals were dried thoroughly to obtain the desired product (yield: 564 mg, 91%).

Yellowish-orange crystals. MS (E§1, t / ζ): 400 (M-H ₂ §O ₄ + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 7.95 (1H, s), 7.43 (1H, d, 1 = 4.4), 7.18 (1H, d, 1 = 2.2), 7.10 (1H, dd, 1 = 2.2, 8.5), 7.01 (1H, d, 1 = 8.5), 6.35 (1H, d, 1 = 4.4), 3 , 83 (3H, s), 3.78 (3H, s), 3.62-3.68 (2H, m), 3.38-3.50 (4H, m), 2.833.07 (6H, m )

Preparation of (Ζ) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] thiophen-2yl} acrylonitrile nitrate (compound 102).

To compound 9 (500 ml) was added 0.1 mol / L sulfuric acid (12.70 mg) and purified water (12.30 ml) and the mixture was heated to dissolve (outside temperature: 90 ° C). The solution was again brought to room temperature and allowed to stand overnight. Precipitated crystals are collected by filtration and the recovered crystals are washed successively with a small amount of purified water and hexane. The crystals were dried thoroughly to obtain the desired product (yield: 530 mg, 91%).

Yellow crystals. MS (E§1, t / ζ): 400 (M-HNO3 + H) ⁺ .

Ή-NMR (DMSO-b ₆ ) δ: 9.67 (1H, br.s), 7.98 (1H, s), 7.45 (1H, d, 1 = 4.4), 7.20 ( 1H, d, 1 = 2.2), 7.12 (1H, dd, 1 = 2.2, 8.5), 7.02 (1H, d, 1 = 8.5), 6.42 (1H d, 1 = 4.4), 5.42 (1H, br.s), 3.84 (3H, s), 3.79 (3H, s), 3.75-3.83 (4H, m ), 3.57-3.64 (2H, m), 3.25-3.40 (6H, m).

Preparation of 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldiethylaminoacetate (compound 103).

Compound 6 (3.70 g) was dissolved in pyridine (100 ml) and Ν, Ν'-diethylglycine sodium salt (7.66 g) was added to the solution, followed by stirring at room temperature for 1 h. Then, p -toluenesulfonyl chloride (9.43 g), followed by stirring under reflux for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. Chloroform (1000 ml) was added to the residue, and the mixture was washed with water three times. Check the pH of the aqueous layer using litmus paper and adjust the pH to 4-5 using 1 N. aqueous solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCI3-hexane) to obtain the desired product (yield: 3.62 g, 75%).

Yellow powder. MS (E1, t / z): 484 (M + H) ⁺ .

Ή-NMR (SPS1 ₃ ) δ: 7.36 (1H, d), 7.22 (1H, d, 1 = 4.6), 7.13 (1H, dd, 1 = 2.2, 8.5 ), 7.04 (1H, d, 1 = 2.2), 6.87 (1H, d, 1 = 8.5), 6.05 (1H, d, 1 = 4.4), 5.03 -5.07 (1H, m), 3.94 (3H, s), 3.91 (3H, s), 3.52-3.58 (2H, m), 3.34 (2H, s), 3.25-3.31 (2H, m), 2.67 (4H, q, 1 = 7.1), 2.02-2.07 (2H, m), 1.82-1.90 (2H , m) 1.07 (6H, t, 1 = 7.1).

Preparation of 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yldimethylaminoacetate hydrochloride (compound 104).

Ethanol (5 ml) and 12N were added to compound 62 (150 mg). hydrochloric acid (28 μl) and the mixture is heated to dissolve (outside temperature: 40 ° C). The solution was again brought to room temperature and allowed to stand overnight. The precipitated crystals are separated by filtration and the recovered crystals are recrystallized from isopropanol to obtain the desired product (yield: 78.7 mg, 48.6%).

Yellow powder. MS (E§1, t / ζ): 456 (M-HC1 + H) ⁺ .

Я-NMR (SPS1 ₃ ) δ: 7.37 (1H, d), 7.22 (1H, d, 1 = 4.1), 7.13 (1H, dd, 1 = 2.2, 8.3 ), 7.04 (1H, d, 1 = 2.2), 6.88 (1H, d, 1 = 8.5), 6.07 (1H, d, 1 = 4.1), 5.13 -5.17 (1H, m), 3.94 (3H, s), 3.91 (3H, s), 3.89 (2H, s), 3.55-3.61 (2H, m), 3.25-3.31 (2H, m), 3.02 (6H, s), 2.02-2.12 (2H, m), 1.88-1.96 (2H, m).

Preparation of 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin4-yldiethylaminoacetate hydrochloride (compound 105).

Isopropanol (10 ml) and 12N were added to compound 103 (338 mg). hydrochloric acid (59 μl) and the mixture is heated to dissolve (outside temperature: 80 ° C). The solution was again brought to room temperature and allowed to stand overnight. Precipitated crystals were collected by filtration and the recovered crystals were recrystallized from isopropanol to obtain the desired product (yield: 254.5 mg, 70.0%).

- 25 014555

Yellow powder. MS (Ε8Ι, t / ζ): 484 (M-HC1 + H) ⁺ .

Ή-NMR (СОС1з) δ: 7.38 (1Н, d), 7.22 (1Н, d, 1 = 4.6), 7.14 (1Н, dd, 1 = 2.2, 8.5) 7.05 (1H, d, 1 = 2.2), 6.88 (1H, d, 1 = 8.5), 6.07 (1H, d, 1 = 4.5), 5.10- 5.15 (1H, m), 3.95 (3H, s), 3.91 (2H, s), 3.91 (3H, s), 3.54-3.60 (2H, m), 3 39 (4H, q, 1 = 7.3), 3.26-3.32 (2H, m), 2.07-2.12 (2H, m), 1.88-1.96 (2H, m) 1.48 (6H, t, 1 = 7.3).

Example 2. The effect of eliminating the resistance of cells Α549 / 8Ν-38-4 to an anticancer agent.

The effect of the compound of the present invention on BCRC-mediated resistance to an anticancer agent was studied using human lung cancer cells No. 549 / 8Ν-38-4 (see international publication XVO 2004/069233), which have acquired resistance to the anti-cancer agent due to the expression of SCCR. A549 human lung cancer cells or Α549 / 8Ν-38-4 cells are suspended in Hams E-12 medium containing 10% EVZ, 100 U / ml penicillin and 100 μg / ml streptomycin (10% EVZ / Hams E-12 medium), and the resulting suspension was inoculated into the wells of a 96-well microplate (2x10 ³ cells / 50 μl / well) and then cultured in an atmosphere of 5% CO ₂ at 37 ° C. overnight. Then, a solution of 10% EVZ / Hams E-12 medium (25 μl) containing compounds 1-102 of the present invention was added to each well, and 8Ν-38 was added, then cultivated in an atmosphere of 5% CO ₂ at a temperature of 37 ° C for 48 h. After cultivation is completed, the number of viable cells is counted using a reagent for counting viable cells | Tc1gaCo1og ΟΝΕ (trademark), product of Zakadaki SogrogEop], in accordance with the manufacturer's instructions. Tables 1-4 illustrate the effect of each of the acrylonitrile derivatives on the elimination of resistance of 8Ν-38 cells, which is presented as an indicator of EC ₅₀ . The EC50 value corresponds to the concentration of the acrylonitrile derivative necessary for a 50% reduction in the relative resistance index. Indicators of resistance are obtained by dividing the EC ₅₀ (i.e., the concentration of the anticancer agent necessary for 50% inhibition of cell growth) for Α549 / 8Ν-38-4 cells by the EC ₅₀ for A549 cells (parent cells). The higher the relative resistance index, the higher the level of acquired resistance. The results of the tests showed that each of the compounds of the present invention shows a powerful effect in overcoming the δΝ-38 resistance of Α549 / 8 /-38-4 cells. In the case when each of the acrylonitrile derivatives is used separately, in the absence of 8Ν-38, the growth of both A549 and Α549 / 8Ν-38-4 is not affected. This suggests that the acrylonitrile derivative of the present invention inhibits SCCR, and in this regard, makes it possible to overcome the resistance of cancer cells to an anticancer agent or to potentiate the sensitivity of cancer cells to an anticancer agent.

Table 1

Compound The effect of overcoming the resistance of the EC50 (NT / ml) one 6 2 130 3 32 4 12 5 thirteen 6 10 7 39 8 45 nine 46 10 120 eleven 49 12 58 thirteen 33 14 87 fifteen 200 nineteen 14 twenty 490 21 twenty 22 thirteen 23 58 24 34 25 thirteen 26 75 27 200 28 120 29th 420

- 26 014555

table 2

Compound The effect of overcoming the resistance of the EU ₅ o (ng / ml) thirty twenty 31 37 32 28 33 520 34 58 35 190 36 120 37 120 the 60 39 37 40 75 41 280 42 220 43 160 44 56 45 fifty 46 one hundred 47 thirty fifty 110 51 510 54 36 56 37 59 61 61 44

Table 3

Compound The effect of overcoming the resistance of the EU ₅₀ (NT / ml) 62 62 64 53 65 eleven 66 37 67 one hundred 68 eleven 69 43 70 eleven 71 thirteen 72 eleven 73 eleven 74 21 75 17 76 2 77 110 78 77 79 6 80 nineteen 82 78 83 190 85 230 86 120 87 46 88 70

- 27 014555

Table 4

Compound The effect of overcoming the resistance of the EU ₅₀ (ng / ml) 90 460 91 520 92 41 93 280 95 8 96 120 97 78 98 one hundred 99 63 one hundred 12 101 thirteen 102 17

Example 3. The effect of overcoming the resistance to the anticancer agent of the leukemia cells of P388 mice transduced with the human HRV gene.

Mouse P388 mouse leukemia cells or P388 cells transduced with the human BCCR gene (cells (P388 / BCCR) (see 1P-A-2003-063989) are suspended in 10% ΡΒ8 / ΚΡΜΙ1640, where this medium contains 2-mercaptoethanol (50 μM) and the resulting suspension was added to the wells of a 96-well microplate (1 x 10 ⁴ cells / 50 μl / well) .A solution of each of the compounds 1, 14, 21, 31, 39, and 41 of the present invention and 8 в-38 in 10 was then added to the wells. % ΡΒ8 / ΚΡΜΙ1640 (25 μl) and then cultured in an atmosphere of 5% CO ₂ at a temperature of 37 ° C for 48 hours. After completion of cultivation, the number of life incapable cells using the reagent for counting viable cells Tc1gaCo1og ΟΝΕ, according to the manufacturer's instructions.The results are shown in Fig. 1. Each of the tested compounds of the present invention shows a powerful effect on eliminating the resistance of P388 / SCCR cells to 8Ν-38, but does not affect the sensitivity of P388 cells to 8Ν-38. The use of only one acrylonitrile derivative does not affect the proliferation of P388 cells and P388 / SCCR cells. This indicates that the acrylonitrile derivative of the present invention has a SCCR inhibitory effect.

Example 4. Effect on multidrug resistance of human leukemia cells K562 transduced with ΜΌΚ1 human gene.

Human K562 leukemia cells or K562 cells transduced with the human ΜΌΚ1 gene (Κ562 / клетки cells) (see, ΜιιΙαΙ. Kek., 1998, 401: 133-141) are suspended in 10% ΡΒ8 / ΚΡΜI1640 and the resulting suspension is added to wells 96 -well microplate (1x10 ³ cells / 50 μl / well). Then, paclitaxel solution and each of the compounds listed in the table are added to the wells. 5 and 6, in 10% ^ 8 / ^ 1 ^ 1640 (25 μl), followed by culturing in an atmosphere of 5% CO ₂ at 37 ° C for 72 hours. After cultivation, the number of viable cells was counted using Te technology ( taSo1og ΟΝΕ, according to the manufacturer's instructions. Table. 5 and 6 illustrates the effect of each of the tested acrylonitrile derivatives on multidrug resistance by the evaluation ΕS5 _0. parameter EU ₅₀ corresponding to the concentration of acrylonitrile derivative required for 50% reduction Show As a result, it was shown that most of the acrylonitrile derivatives of the present invention do not affect the resistance of Κ562 / клеток cells to paclitaxel.In addition, when the concentration of the acrylonitrile derivative falls within the concentration range used for this test, the acrylonitrile derivative Reggae does not affect the growth of K562 cells and Κ562 / клеток cells. These data indicate that the acrylonitrile derivative of the present invention does not affect Pglycoprotein and has a high specific identity to HRV.

- 28 014555

Table 5

Compound The effect of overcoming the resistance of the EU ₅₀ (ng / ml) one > 5000 3 > 5000 4 > 5000 5 > 5000 6 > 5000 14 > 5000 17 > 5000 eighteen > 5000 nineteen > 5000 twenty > 5000 21 > 5000 25 > 5000 26 > 5000 27 > 5000 28 > 5000 thirty > 5000 31 > 5000 32 > 5000 33 > 5000 34 > 5000 36 > 5000 38 > 5000 39 > 5000 40 > 5000 41 > 5000 42 > 5000

Table 6

Compound The effect of overcoming the resistance of the EC50 (ng / ml) 43 > 5000 44 > 5000 45 > 5000 46 > 5000 47 > 5000 52 > 5000 53 > 5000 55 > 5000 56 > 5000

Example 5. The effect of the amount of anticancer agent accumulated in cells expressing SCCR.

K562 cells or K562 cells transduced with the human BCCR gene (K562 / BCCR cells) (see 1P-A-2003-063989). suspended in 10% PB8 / KPM11640 (1 ml) (5 × 10 ⁶ cells / ml) and 8Ν-38 and each of compounds 1, 39 and 46 of the present invention (final concentration: 500 ng / ml) were added to the resulting suspension, then incubation for 30 minutes at a temperature of 37 ° C. After centrifugation (2 ° C, 1400hd, 1 min), the resulting supernatant is removed. Ice-cooled B8A containing 1% BCA was added to the resulting cell pellet, and the cells were resuspended, followed by centrifugation (2 ° C, 1400 xd, 1 min) to wash the cells. The indicated washing procedure is repeated once more, followed by the addition of B8A (250 μl) and sonication of the cells. Methanol (250 μl) and a 10% zinc sulfate solution (10 μl) were added to the resulting mixture of the cells subjected to ultrasound, and the resulting mixture was stirred, followed by centrifugation (2 ° C, 12, 500 xd, 5 min) and then the supernatant was collected. The supernatant thus obtained was added to the wells of a white 96-well plate to measure the fluorescence intensity (200 μl / well) and then the amount of 8Ν-38 contained in the supernatant was measured using a microplate fluorimeter [8RESTAX ΟΕΜΙΝΙ X8 (trademark), product Mo1esi1ag Esu1SS5 | (8Ν-38: excitation wavelength of 380 nm, emission wavelength of 560 nm) to calculate the amount of intracellular accumulation of 8Ν-38. As can be seen from the data of FIG. 2, the acrylonitrile derivative of the present invention increases the amount of 8Ν-38 accumulated in K562 / SCCR cells. Conversely, the amount of 8Ν-38 accumulated in K562 cells (starting cells), in which SCCR is not expressed, remains virtually unaffected. This result makes it possible to assume that the derivative

- 29 014555 the acrylonitrile of the present invention inhibits SCCR and increases the level of intracellular accumulation of an anticancer agent.

Example 6. The effect of overcoming resistance to the anticancer agent ίη νίνο.

Cancer cells of human colon HCT116 cells or HCT116 cells transduced gene VSKR (HCT116 / VSKR cells) (obtained from Όγ. UokYkahn διίβίιηοίο. Tys Sapseg S11sto111sgaru SsgIsg about £ 1arapsks ΡοιιηάηΙίοη £ og Sapseg Keksagsy) were transplanted subcutaneously (3x10 ⁶ cells / 0, 1 ml / mouse) in the inguinal region of 6-week-old male VLV / s mice (5 mice / group). Once the tumor size is set at 1 / 2ab ² (a - a longer tumor diameter b -. Shorter tumor diameter) and becomes equal to approximately 150-200 mm ^3. each of the compounds of the present invention. shown in tables 7 and 8 (6.3. 12.5 or 25 mg / kg / day) and CPT-11 (10 mg / kg / day). administered intravenously to mice once a day for seven days. For an introduction. each of the compounds of the present invention is dissolved in physiological saline or in a mixture of ethanol. polyoxyethylene (20) sorbitan monooleate [Tween 80 (trademark). Tokuο Kaka product Κοβ \ Ό ^ .. BJ.] and 5% glucose (zanol / tween 80/5% glucose = 5: 5: 90). and CPT-11 is dissolved in physiological saline. Animals in the control group are administered only one solvent. At 21 days from the start of administration. tumors from each mouse are excised. 1K tumor growth inhibition rate (%) was weighed and calculated using the following equation.

Tumor growth inhibition rate 1K (%) = (1-average tumor mass in each administration group / average tumor volume in the control group) x100. The results are presented in table. 7 and 8. As can be seen from table. 7 and 8. Acrylonitrile derivatives of the present invention inhibit SCCR also такжеη νίνο. showing the effect of eliminating resistance to an anti-cancer agent.

Table 7

Transplant Compound Dose Tumor mass ΙΚ ovannye (mg / kg / day) (g) (%> cancerous Compound CPT average cells -eleven value ± speed 23 12, 5 10 1.21 ± 0.17 12, 3 25 10 0.721 ± 0.11 ** 48, 8 HCT116 / HRVR 31 12, 5 10 0.74 ± 0.06 ** 46, 6 25 10 0.67 + 0.18 ** 51, 1 Solvent 0 10 1.20 ± 0.15 13,2 0 0 1.38 + 0.35

HCT116 Solvent 0 10 0.37 ± 0.08 72.0

0 1.31 + 0.20 ** P <0.01: significant difference relative to option: solvent + SRT-11 (HCT116 / VSKR) (Dunnet test).

Table 8

Transplant Compound Dose Weight ΙΚ these cancers (mg / kg / day> tumors (g) (%) cells Compounds CPT average e -eleven value ± speed thirteen 12, 5 10 0.87 + 0.18 31, 7 25 10 0.83 + 0.08 * 35.0 14 12, 5 10 0.79 + 0.14 * 37.7 25 10 0.70 ± 0.10 ** 45.1 HCT116 / VSKR 32 6, 3 10 0.75 ± 0.24 40, 8 12, 5 10 0.52 + 0.11 59.0 46 12.5 10 0.79 ± 0.21 37, 7 25 10 0.67 + 0.07 47, 7

Solvent 0 10 1.10 + 0.10 13.3

0 1.25 + 0.15 ** P <0.05. ** P <0.01: significant difference with respect to option: solvent + SRT-11 (HCT116 / VSKR) (Dunnet test)

Example 7. The following ingredients are mixed and compressed into tablets. Table 9

Compound 1 100 mg Lactose 100 mg Potato starch 3 9 mg Microcrystalline cellulose 30 mg Synthetic aluminum silicate 30 mg Calcium stearate 1 mg Total 300 mg

Claims (15)

CLAIM 1. The use of an acrylonitrile derivative represented by the formula (1) or a salt thereof, where one of the K ₁ and K ₂ is a cyano group and the other is a hydrogen atom; Ar ¹ means a group selected from the groups represented by formulas (2) - (4): where K- and K ₈ , which may be the same or different, each means a hydrogen atom, a halogen atom, a linear or branched C _1-6 alkoxy group, or a C _3-6 cycloalkyloxy group; A means an oxygen atom, a sulfur atom or ΝΚ ₉ ; and K ₉ means a hydrogen atom or a linear or branched C _1-6 alkyl group; Ar ² means C _113-14 aryl group containing a condensed ring, which may be substituted by a halogen atom or a group selected from the groups represented by formulas (5) - (15): (11) (12) (13) ¢ 14) (15) where K ₃ means a hydrogen atom, an oxygen atom (in the form of Ν-oxide), a linear or branched C _1-6 alkyl group, a linear or branched C _1-6 alkoxy group , C _3-6 cycloalkyloxy group, halogen atom, nitro group, methylsulfanyl group, linear or branched C _1-6 hydroxyalkyl group, C _6-14 aryl group, which may contain as a substituent nitro or amino group, or ΝΚ ₅ (Κ ₆ ); K ₅ and K ₆ , which may be the same or different, each means a hydrogen atom, a linear or branched C1-6 alkyl group, which may contain as a substituent a C1-6 alkylamino group or a di (C _1-6 alkyl) amino group, linear or branched A C _1-6 hydroxyalkyl group, a C _6-14 aryl group which may contain as its substituent a nitro group or an amino group, or an alicyclic or aromatic heterocyclic compound containing at least one heteroatom in the ring; K ₅ and Kb can form, together with the adjacent nitrogen atom, a heterocyclic ring selected from the group consisting of pyrrolidine, imidazole, pyridine, piperidine, pyrimidine, piperazine, morpholine, indole, benzimidazole, benzpyrazole and quinoline, which may contain as substituent a hydroxy group, a linear or branched C 1-6 alkyl group, or a linear or branched C 1-6 hydroxyalkyl group; and a hydroxyl group of a linear or branched C _1-6 hydroxyalkyl group or heterocyclic ring substituted by a hydroxyl group or a linear or branched C _1-6 hydroxyalkyl group, may form an ester bond with the phosphoric acid group or its salt, or with an acyl group which may contain as Under-di (C1-6 alkyl) amino group, a phenylcarbamoyl group which may have a C ₁ - ₆ alkylamino or di (C _1-6 alkyl) amino group as a substituent; Wc _1-6 alkylcarbamoyl group which may have a C _1-6 alkylamino group or di _(C1-6 alkyl) amino group as a substituent, ^ №diS _1-6 alkylcarbamoyl group which may have a C _1-6 alkylamino group or di ( C ₁ - ₆ alkyl) amino group as a substituent, Ν-piperidinokarbonilnuyu group which may comprise pyrrolidine, piperidine or piperazine as a substituent, or 4piperidinopiperidin-1-yl group; K ₄ means a hydrogen atom, a linear or branched C _1-6 alkyl group; a phenyl group which may contain as a substituent a halogen atom, a linear or branched C _1-6 alkoxy group, or a C3-6 cycloalkoxy group; or benzyl group; X means a carbon atom, CH or a nitrogen atom, provided that when A represents an oxygen atom, X cannot be a nitrogen atom; and A, K-, K ₈ and K ₉ are as defined above; as a DSRC inhibitor. - 31 014555 2. Use of an agent for elimination of resistance to an anti-cancer agent mediated by DSRC or an agent for potentiating the anti-cancer effect of an agent in cancer, which is characterized by the presence of acquired drug resistance mediated by DSRC, which includes an acrylonitrile derivative according to claim 1 or its salt as an active ingredient. 3. An anti-cancer composition, where cancer is characterized by the presence of acquired drug resistance mediated by DSRC, containing an acrylonitrile derivative according to claim 1 or its salt, and an anti-cancer agent that serves as a substrate for DSRC. 4. The use of an acrylonitrile derivative according to claim 1 or a salt thereof for the preparation of a DCCS inhibitor as an agent for elimination of resistance to an anticancer agent mediated by DSRC, or an agent for potentiating the anticancer effect of the agent, where the cancer is characterized by the presence of acquired drug resistance mediated by DSRS. 5. A method of treating cancer, which is characterized by the presence of acquired resistance to the drug mediated by DCCR, including the introduction of an acrylonitrile derivative according to claim 1 or its salt. 6. The use of a derivative of Acrylonitrile represented by the formula (1A) V X NDag ¹ (1a) (Eli2) or its salt, where one of K1 and K2 is cyano and the other is hydrogen; Ar ¹ means a group selected from the groups represented by formulas (2) - (4): where K ₇ and K ₈ , which may be the same or different, each means a hydrogen atom, a halogen atom, a linear or branched C _1-6 alkoxy group or a C _3-6 cycloalkyloxy group; And means an oxygen atom, a sulfur atom or IR _E ; and K9 means a hydrogen atom or a linear or branched C1-6 alkyl group; Ar ² represents C _{£ 0-} 1 ₄ aryl group having a condensed ring which may be substituted with a halogen atom or a group selected from groups represented by formulas (5) - (15) ^{11 (11) (12) (} 13) ( 14) (15) where R _3a is a hydrogen atom (Ar ¹ represents a group represented by the formula (3) or (4)), linear or branched C1 _-6 alkyl group, a linear or branched C1 _-6 alkoxy, C _3-6 cycloalkyloxy , halogen atom, nitro group, methylsulfanyl group, linear or branched _C1-6 hydroxyalkyl group, C _{6- £ 4} aryl group, which toraya may be substituted by a nitro group or an amino group, or IR ₅ (K ₆ ); K ₃ is a hydrogen atom, a linear or branched C1 _-6 alkyl group, a linear or branched C1 _-6 alkoxy group, a C _3-6 cycloalkyloxy group, a halogen atom, a nitro group, a methylsulfanyl group, a linear or branched C1 _-6 hydroxyalkyl, C 1 _{6- 4} aryl group, which may be substituted by an amino group, or IR ₅ (K ₆ ); K _3c means a hydrogen atom (Ar ¹ means a group represented by the formula (3) or (4)), an oxygen atom (as a Ν-oxide), a linear or branched C С _-6 alkyl group, a linear or branched C 1 _-6 alkoxy group, C _3-6 cycloalkyloxy group, halogen atom, nitro group, methylsulfanyl group, linear or branched C 1 _-6 hydroxyalkyl group, C _{6- £ 4} aryl group, which may be substituted with a nitro group or amino group, or ₅ ( ₆ ); each of K _3b , K _3e and K _{3 означает} means a hydrogen atom, an oxygen atom (in the form of Ν-oxide), a linear or branched C 1-6 alkyl group, a linear or branched C 1-6 alkoxy group, C 3-6 cycloalkyloxy group, a halogen atom, a nitro group, methylsulfanyl a group, a linear or branched C1-6hydroxyalkyl group, or a C6-14 aryl group, which may be substituted by an amino group, or a NC. ₅ (K. ₆ ); To ₅ and R _6, which may be identical or different, each represents a hydrogen atom, a linear or branched _C1-C6 alkyl group which may be substituted by a C _{£ -6} alkylamino or di (C1 _-6 alkyl) amino group, a linear or branched C _{£ -6} hydroxyalkyl - 32 014555 group, C 6-14 aryl group, which may contain a nitro group or an amino group as a substituent, or an alicyclic or aromatic compound having at least one heteroatom in the ring; K ₅ and K ₆ can form together with the adjacent nitrogen atom a heterocyclic ring selected from the group consisting of pyrrolidine, imidazole, pyridine, piperidine, pyrimidine, piperazine, morpholine, indole, benzimidazole, benzpyrazole and quinoline, which may contain hydroxy as a substituent a linear or branched _C1-6 alkyl group or a linear or branched _C1-6 hydroxyalkyl group; and a hydroxyl group of a linear or branched _C1-6 hydroxyalkyl group or a heterocyclic ring substituted by a hydroxyl group or a linear or branched _C1-6 hydroxyalkyl group may form an ester bond with the phosphoric acid group or its salt, or with an acyl group which may contain Under-di (C1-6 alkyl) amino group, a phenylcarbamoyl group which may contain C1 _-6 alkylamino or di (C1 _-6 alkyl) amino group as a substituent; №S1 _-6 alkylcarbamoyl group which may have a C1 _-6 alkylamino or di (C1 _-6 alkyl) amino group as a substituent, ^ №di-C1 _-6 alkylcarbamoyl group which may have a C _3-6 alkylamino group or di (C1 _{- 6} alkyl) amino group as a substituent, Ν-piperidinocarbonyl group which may contain a pyrrolidine, piperidine or piperazine as a substituent, or a 4-piperidinopiperidin-1-yl group; K ₄ means a hydrogen atom, a linear or branched C _1-6 alkyl group, a phenyl group which may contain as a substituent a halogen atom or a linear or branched C 1-6 alkoxy group or a C 3-6 cycloalkyloxy group; or benzyl group; X means a carbon atom, CH or a nitrogen atom, provided that when A represents an oxygen atom, then X cannot be a nitrogen atom; and A, K ₇ , K _8, and K ₉ are as defined above as a DSRC inhibitor. 7. The use of a derivative of Acrylonitrile or its salt selected from (2) -2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile, (2) -2- (3,4-dimethoxyphenyl) -3-pyridine -3-ylacrylonitrile, (Ζ) -3- (3,4-dimethoxyphenyl) -2-pyridin-3-acrylonitrile, (Ζ) -3- (3,4-dimethoxyphenyl) -2-pyridin-2-ylacrylonitrile, ^ ) -2- (3,4-dimethoxyphenyl) -3-pyridin-2-ylacrylonitrile, (E) -3- (3,4-dimethoxyphenyl) -2-thiophen-2-ylacrylonitrile, ^) -2- (3, 4-dimethoxyphenyl) -3-quinolin-4-ylacrylonitrile, (E) -2-benzotriazol-1 -yl-3 - (3,4-dimethoxyphenyl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3 - quinolin-2-yl acrylonitrile, (U) -2-pyridin-3 -yl-3 -x nolin-4-yl acrylonitrile, (E) -3-benzo [b] thiophen-3 -yl-2-thiophen-2-ylacrylonitrile, (Ζ) -3-benzofuran-2-yl-2- (3,4-dimethoxyphenyl ) acrylonitrile, ^) - 2- (3,4-dimethoxyphenyl) -3-naphthalen-2-ylacrylonitrile, ^) - 2- (3,4-dimethoxyphenyl) -3-phenanthrene-9-ylacrylonitrile, as an inhibitor of VSCR. 8. Use of an agent to eliminate resistance to an anti-cancer drug mediated by DSRC or an agent for potentiating an anti-cancer effect on cancer having acquired drug resistance mediated by DSRC, which includes the acrylonitrile derivative of claim 6 or 7 or its salt as an active ingredient. 9. An anticancer composition intended for the treatment of cancer, which is characterized by the presence of acquired drug resistance mediated by DSRC, containing the acrylonitrile derivative according to claim 6 or 7 or its salt and an anti-cancer agent, which serves as a substrate for DSRC. 10. Use of an acrylonitrile derivative according to claim 6 or 7 or a salt thereof for the preparation of a DSRC inhibitor as an agent for eliminating resistance to an anticancer agent mediated by DSCR or an agent for potentiating the anticancer effect of an agent against cancer having acquired DSRC mediated resistance. 11. A method of treating cancer, which is characterized by the presence of acquired drug resistance mediated by DSRC, comprising administering an acrylonitrile derivative according to claim 6 or 7 or a salt thereof. 12. Derivative of acrylonitrile or its salt selected from ^) - 2- (3,4-dimethoxyphenyl) -3- (5-nitrothiophen-2-yl) acrylonitrile, ^) -3- (5-bromothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) - 3- (5-aminothiophen-2-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (5-piperidin-1-ylthiophen-2-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylthiophen-2-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) thiophen-2-yl] acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2-hydroxyethyl) methylamino] thiophen-2-yl} Acrylonitrile, - 33 014555 (^) -2- (3,4-dimethoxyphenyl) -3- [5- (4-methylpiperazin-1-yl) thiophen-2-yl] acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazin-1-yl] thiophen-2-yl} acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylaminoethyl) methylamino ] thiophen-2-yl} acrylonitrile, mono- (1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) phosphate, mono- (1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl} piperidin-4-yl) succinate, ^) - 2- (3,4 -dimethoxyphenyl) -3- (5-nitrofuran-2-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (5-hydroxymethylfuran-2-yl) acrylonitrile, ^) -2- (3 , 4-dimethoxyphenyl) -3- [5- (3-nitrophe yl) furan-2-yl] acrylonitrile, () -3- [5- (3-aminophenyl) furan-2-yl] -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) -2- (3, 4-dimethoxyphenyl) -3- (5-piperidin-1-ylfuran-2-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (5-morpholin-4-ylfuran-2-yl) Acrylonitrile, ^) - 2- (3,4-dimethoxyphenyl) -3- [5- (4-hydroxypiperidin-1-yl) furan-2-yl] acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) - 3- [5- (4-methylpiperazin-1-yl) furan-2-yl] acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- {5- [4- (2-hydroxyethyl) piperazine- 1-yl] furan-2-yl} acrylonitrile, Ν-oxide ^) - 2- (3,4-dimethoxyphenyl) -3-pyridin-4-ylacrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3 - (6-methoxypyridin-3 ) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (1H-pyrrol-2-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- (3H-imidazol-4 -yl) acrylonitrile, ^) - 3- (3-benzyl-2-methylsulfanyl-3H-imidazol-4-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl ) -3- (4-methyl-2-phenylthiazol-5-yl) acrylonitrile, ^) -2- (3,4-dimethoxyphenyl) -3- {5 - [(2-dimethylaminoethyl) methylamino] furan-2-yl } acrylonitrile, mono- (1- {5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) succinate, mono- (1- { 5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] furan-2-yl} piperidin-4-yl) phosphate, ^) - 3- (5-bromofuran-2-yl) - 2- (3,4-dimethoxyphenyl) acryl onitrile, (Ζ) -3- (3,4-dimethoxyphenyl) -2-thiophene-3-acrylonitrile, 1- [5 - [^) -2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophene 2-yl] piperidin-4-yl Ν- (2-diethylamino ethyl) succinamate, 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl No. (3-diethylaminopropyl) succinamate, 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yldimethylaminoacetate, 1- [5 - [^) - 2-cyano-2 - (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl [1,4 '] bipiperidinyl 1'-carboxylate, 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl 4- [1,4 '] bipiperidinyl-1'-yl- 4-oxobutylate, (Ζ) -3-benzo [b] thiophen-3-yl-2- (3,4-dimethoxyphenyl) acrylonitrile, () -2- (3,4-dimethoxyphenyl) -3- (1 - methyl 1H-benzimidazol-2-yl) acrylonitrile, () -2- (3,4-dimethoxyphenyl) -3- (1-methyl-1H-indole-3 -yl) acrylonitrile, ^) - 3- (2 -chloroquinolin-3-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) -2-benzofuran-3 -yl-3 - (3,4-dimethoxyphenyl) acrylonitrile, ^) - 3- (2-chloro -6-methoxyquinolin-3-yl) -2- (3,4-dimethoxyphenyl) acrylonitrile, (E) -2-benzothiazol-2-yl-3- (3,4-dimethoxyphenyl) acrylonitrile, ^) - 3- ( 2,3-dihydrobenzofuran-5 ) -2- (3,4-dimethoxyphenyl) acrylonitrile, ^) - 2- (3,4-dimethoxyphenyl) -3- [5- (4-fluorophenyl) isoxazol-3-yl] acrylonitrile, ^) -2- ( 3,4-dimethoxyphenyl) -3- [5- (4-methoxyphenyl) isoxazol-3-yl] acrylonitrile, ^) - 3- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-2- Ilkrilonitrile, ^) - 3- (2-chloro-6-methoxyquinolin-3-yl) -2-pyridin-3-ylacrylonitrile, (E) -3- (2-chloro-6-methoxyquinolin-3-yl) -2 -thiophen-2-yl acrylonitrile, ^) - 3- (2-chloro-6-methoxyquinolin-3-yl) -2-thiophen-3-ylacrylonitrile, (E) -2-benzotriazol-1 -yl-3 - (2 -chloro-6-methoxy-quinolin-3-yl) acrylonitrile, (E) -2-benzothiazol-2-yl-3- (2-chloro-6-methoxy-quinolin-3-yl) acrylonitrile, (Ζ) -2-pyridium n-2 -yl-3-quinolin-4-ylacrylonitrile, (E) -3-quinolin-4 -yl-2-thiophen-2-ylacrylonitrile, () -3-quinolin-4-yl-2-thiophene 3-yl acrylonitrile, (E) -3-benzo [b] thiophen-3-yl-2-benzothiazol-2-ylacrylonitrile, ^) - 3-benzofuran-2-yl-2-benzofuran-3-ylacrylonitrile, (E) -2-Benzothiazol-2-yl-3 - (1-methyl-1H-indol-3-yl) acrylonitrile, ^) - 3- (10-chloro-trans-9-yl) -2- (3,4-dimethoxyphenyl) Acrylonitrile, 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl diethylaminoacetate, 1- [5 - [^) -2- cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl diethylcarbamate, 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thio phen-2-yl] piperidin-4-yl-L- (2 diethylaminoethyl) -Y-methylsuccinamate and 1- [5 - [^) - 2-cyano-2- (3,4-dimethoxyphenyl) vinyl] thiophen-2-yl] piperidin-4-yl No. (4-diethylaminophen - 34 014555 nil) succinammate. 13. Drug comprising as an active ingredient the compound according to claim 12 or a salt thereof. 14. A pharmaceutical composition comprising a compound according to claim 12 or a salt thereof and a pharmaceutically acceptable carrier. 15. The use of compounds under item 12 or its salts to obtain the drug. Connection 1 5№-E8 (ng / ml) 5M-38 (ng / mg) P38 & 0 ng / ml test compound P388: 500 ng / ml test compound P38B / VSNAR: 0 ng / ml of the tested compound P38B / VOYR: 50 ng / ml of the tested compound P388 / VOYAR; 500 ng / ml test compound